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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. C19 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, pregnenolone. Retinoic acid and vitamin D are not derived from pregnenolone, but from vitamin A and cholesterol respectively.

Structure of pregnenolone Pregnenolone: produced directly from cholesterol, the precursor molecule for all C18, C19 and C21 steroids
Structure of progesterone 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
Structure of aldosterone Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake
Structure of testosterone Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone
Structure of estradiol Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics
Structure of cortisol 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 (also referred to as nuclear receptors, NR). 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 T3 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 TRα and the other encoding TRβ. 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 C18, C19 and C21 steroids involves the cleavage of a 6-carbon 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 inner mitochondrial membrane of steroid-producing cells, but not in significant quantities in other cells. In order for cholesterol to be used for steroid hormone biosynthesis it must be transported from the outer mitochondrial membrane to the inner membrane. This transport process is mediated by steroidogenic acute regulatory protein (StAR) and this transport process represents the rate-limiting step in steroidogenesis. The StAR protein is encoded by the STAR gene which is located on chromosome 8p11.23 and is composed of 7 exons that encode a 285 amino acid protein.

Mitochondrial 20,20-desmolase (P450ssc) is a complex enzyme system consisting of a cytochrome P450 family member enzyme and the proteins ferredoxin reductase (also known as adrenodoxin reductase) and ferredoxin 1 (also known as adrenadoxin). The cytochrome P450 enzyme is encoded by the CYP11A1 gene (see the Cytochrome P450 page for description of CYP nomenclature). The overall cholesterol side-chain cleavage occurs through a series of three reactions all catalyzed by the desmolase complex. The activity of each of these components is increased by two principal cAMP- and PKA-dependent 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 (CYP11A1) for desmolase. This gene contains a cAMP regulatory element (CRE) that binds the transcription factor identified as cAMP-response element binding protein, CREB. CREB is phosphorylated by PKA in the cytosol and then migrates to the nucleus where it binds to CREs in target genes such as CYP11A1. The consequences of CREB binding to CYP11A1 are increassed rates 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. 17α-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 17α-hydroxylase is also identified as P450c17). The officially preferred nomenclature for the cytochrome P450 class of enzymes is to use the prefix CYP. Thus, 17α-hydroxylase is identified as CYP17A1. There are currently 57 identified CYP genes in the human genome.

Primary Enzyme Activities of Steroid Hormone Biosynthesis

Common Name(s) Gene ID Activities Primary Site of Expression
steroidogenic acute regulatory protein STAR mediates transport of cholesterol from outer mitochondrial membrane to the inner membrane all steroidogenic tissues except placenta and brain
desmolase, P450ssc CYP11A1 cholesterol-20,23-desmolase steroidogenic tissues
3β-hydroxysteroid dehydrogenase type 1 HSD3B2 3β-hydroxysteroid dehydrogenase steroidogenic tissues
P450c11 CYP11B1 11β-hydroxylase only in zona fasciculata and zona reticularis of adrenal cortex
P450c17 CYP17A1 two activities: 17α-hydroxylase and 17,20-lyase steroidogenic tissues
P450c21 CYP21A2 21-hydroxylase not expressed in the zona reticularis
aldosterone synthase CYP11B2 18α-hydroxylase exclusive to zona glomerulosa of adrenal cortex
estrogen synthetase CYP19A1 aromatase gonads, brain, adrenals, adipose tissue, bone
17β-hydroxysteroid dehydrogenase type 3 HSD17B3 17-ketoreductase steroidogenic tissues
sulfotransferase SULT2A1 sulfotransferase liver, adrenals
5α-reductase type 2 SRD5A2 5α-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. As indicated earlier, in order for cholesterol to be converted to pregnenolone in the adrenal cortex it must be transported from the outer mitochondrial membrane to the inner where CYP11A1 resides and this transport process is mediated by the transport protein StAR.

Adrenal steroid hormone synthesis

Synthesis of the various adrenal steroid hormones from cholesterol. Only the terminal hormone structures are included. 3β-DH and Δ4,5-isomerase are the two activities of 3β-hydroxysteroid dehydrogenase type 1 (gene symbol HSD3B2), P450c11 is 11β-hydroxylase (CYP11B1), P450c17 is CYP17A1. CYP17A1 is a single microsomal enzyme that has two steroid biosynthetic activities: 17α-hydroxylase which converts pregnenolone to 17-hydroxypregnenolone (17-OH pregnenolone) and 17,20-lyase which converts 17-OH pregnenolone to DHEA (dehydroepiandrosterone). P450c21 is 21-hydroxylase (CYP21A2, also identified as CYP21 or CYP21B). Aldosterone synthase is also known as 18α-hydroxylase (CYP11B2). The gene symbol for sulfotransferase is SULT2A1. Click here for a larger format picture that contains all the intermediate structures.

Conversion of pregnenolone to progesterone requires the two enzyme activities of HSD3B2: the 3β-hydroxysteroid dehydrogenase and Δ4,5-isomerase activities. Zona glomerulosa cells lack the CYP17A1 that converts pregnenolone and progesterone to their C17 hydroxylated analogs. Thus, the pathways to the glucocorticoids (deoxycortisol and cortisol) and the androgens (DHEA and androstenedione) are blocked in these cells. Zona glomerulosa cells are unique in the adrenal cortex in that they are the only cells expressing the enzyme responsible for converting corticosterone to aldosterone, the principal and most potent mineralocorticoid. This enzyme is P450c18 (or 18α-hydroxylase, CYP11B2), also more commonly 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 (CYP11B2) that converts corticosterone to aldosterone, and thus these tissues produce only the weak mineralocorticoid corticosterone. However, both these zones do contain the CYP17A1 missing in zona glomerulosa and thus produce the major glucocorticoid, cortisol. Zona fasciculata and zona reticularis cells also contain CYP17A1, 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 (CYP11A1) 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 two compounds then re-enter the mitochondrion, where the enzymes are located for tissue-specific conversion to glucocorticoids (cortisol) or mineralocorticoids (aldosterone), respectively.

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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 α-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; 11-deoxycorticosterone) 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 (minerals). 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 (Na+) reabsorption in the connecting tubule (CNT) and cortical collecting duct of the nephrons in the kidneys. Within these regions of the nephron aldosterone induces the expression of the Na+,K+-ATPase subunit genes (ATP1A1 and ATP1B1), the genes encoding the subunits (SCNN1A, SCNN1B, and SCNN1C) of the epithelial sodium channel (ENaC), and the SLC12A3 gene (encoding the Na+-Cl cotransporter, NCC). The net effect of the induction of these transporter genes by aldosterone is enhanced Na+ reabsorption as a function of the apical membrane localized ENaC and NCC transporters and delivery to the blood via the action of the basolateral membrane localized Na+,K+-ATPase. Secondary to the Na+ uptake is efflux of K+ to the tubular lumen. Aldosterone also enhances the excretion of potassium (K+) and hydrogen (H+) ions from the collecting duct which is a compensating action to counter the accumulation of the positive charge imparted by increased Na+. However, the action of aldosterone is also 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 (Cl) and water resulting in the expansion of extracellular volume.

Androgens: The androgens, androstenedione and DHEA, circulate bound primarily to sex hormone-binding 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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Regulation of Adrenal Steroid Synthesis

Adrenocorticotropic hormone (ACTH), synthesized by corticotropic cells of the anterior pituitary, regulates steroid hormone production in the adrenal cortex, primarily within cells of the zona fasciculata and zona reticularis. ACTH binds to the ACTH receptor present in the plasma membrane of adrenal cortical cells. The ACTH receptor is identified as MC2R for melanocortin-2 receptor. The ACTH receptor is a Gs-type G-protein coupled receptor (GPCR) and ACTH binding triggers activation of adenylate cyclase, elevation of cAMP, and increased PKA. Activation of PKA leads to phosphorylation and activation of cholesterol ester esterase leading to increased concentrations of free cholesterol, the substrate for steroid hormone synthesis. The effect of ACTH on the production of cortisol is particularly important, with the result that a classic feedback loop results in cortisol inhibiting ACTH release from the pituitary. The ACTH-cortisol regulatory loop is required to the regulation of the circulating levels of corticotropin releasing hormone (CRH), ACTH, and cortisol.

Aldosterone secretion from the zona glomerulosa is stimulated by an entirely different mechanism. Angiotensin II, and to a lesser extent angiotensin III, stimulate zona glomerulosa cells by binding a plasma membrane G-protein coupled receptor (angiotensin receptor 1; AT1) that is coupled to a Gq-type G-protein that activates phospholipase Cβ (PLCβ). Angiotensin II is derived from the liver synthesized precursor protein, angiotensinogen, via the concerted actions of kidney-derived renin and the membrane-bound Zn2+-dependent protease, angiotensin-converting enzyme (ACE). Angiotensin III is derived from angiotensin II via the action of another membrane-bound Zn2+-dependent protease, glutamyl aminopeptidase. Upon angiotensin II binding to AT1 there is a resultant increase in PKC activity and an elevation in intracellular Ca2+ levels. These events lead to increased CYP11A1 (P450ssc) activity and increased production of aldosterone. In the kidney, aldosterone regulates sodium (Na+) retention by stimulating the expression of the mRNA for the Na+/K+–ATPase responsible for the re-accumulation 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. This hormonal regulatory process is referred to as the renin-angiotensin-aldosterone system, RAAS. Among the drugs most widely employed to lower blood pressure are the angiotensin converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARBs). All drugs that are ACE inhibitors end with the suffix –pril and all drugs that are ARBs end with the suffix –sartan. The ACE inhibitors are potent competitive inhibitors of the enzyme that converts angiotensin I to the physiologically active angiotensin II. 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 secretory 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 three enzyme complexes leading to glucocorticoid production, large amounts of the most important androgen, dehydroepiandrosterone (DHEA), are produced. These mutations lead to hirsutism and other masculinizing changes in secondary sex characteristics in females as is seen in several of the congenital adrenal hyperplasias, CAH.

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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 1–2 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 (11β-hydroxylase). The majority of CAH cases (90–95%) 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 3β-hydroxysteroid dehydrogenase (HSD3B2), placental aromatase or P450-oxidoreductase (POR). An additional CAH is caused by mutations that affect either the 17α-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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Glucocorticoid Synthesis in the Liver, Adipose Tissue, & Skeletal Muscle

Liver, adipose tissue, and skeletal muscle convert the inactive glucocorticoids, cortisone and 11-dehydrocorticosterone, to the active hormones cortisol and corticosterone via a pathway that is directly controlled by metabolic reactions taking place within the endoplasmic reticulum, ER. The ER has been recognized for many years as a key organelle responding to changes in nutrient levels. Of particular significance to the role of the ER in nutrient responsiveness are cells of liver (hepatocytes), adipose tissue (adipocytes), and the pancrease (β-cells). Extreme metabolic conditions that include both over feeding and prolonged fasting/starvation result in the activation of ER stress response pathways. One major ER stress induced response to aberrant levels of nutrition is the unfolded protein response (UPR). Activation of the UPR can eventually result in insulin resistance, as is typical in type 2 diabetes, apoptosis, and excess inflammatory responses. The consumption of excess calories is also associated with the stimulation of the ER-localized pathways of intracellular glucocorticoid activation in many different cells, but particularly in the liver and adipose tissue. The over feeding induced increases in intracellular glucocorticoids plays an important role in the pathology of obesity, the metabolic syndrome, and type 2 diabetes.

With respect to the ER and intracellular glucocorticoid activation the critical components are glucose-6-phosphate and the ER-localized glucose-6-phosphate dehydrogenase activity, which is referred to as the H form of the glucose-6-phosphate dehydrogenase. The G form of glucose-6-phosphate dehydrogenase is the cytoplasmic enzyme that serves a critical function in the oxidative reactions of the pentose phosphate pathway. The H form of glucose-6-phosphate dehydrogenase activity is identified as hexose-6-phosphate dehydrogenase (encoded by the H6PD gene) and also as glucose 1-dehydrogenase. Whereas the G6PD encoded enzyme resides in the cytosol, the H6PD encoded enzyme resides within the ER and the sarcoplasmic reticulum (SR). The H6PD gene is located on chromosome 1p36.22 and is composed of 7 exons that generate two alternatively spliced mRNAs encodeing precursor proteins of 802 amino acids and 791 amino acids. The H6PD gene is not expressed in erythrocytes. Within the ER, hexose-6-phosphate dehydrogenase converts glucose-6-phosphate and NADP+ to 6-phosphogluconate and NADPH in a single step, whereas this process in the cytosol requires two separate enzymes. In addition to glucose-6-phosphate, H6PD can metabolize other hexose-6-phosphates, glucose-6-sulfate, and glucose. One of the primary functions of the ER- and SR-localized NADPH is to maintain redox homeostasis within these organelles. Loss of ER redox homeostasis can lead to ER stress and induction of the unfolded protein response (UPR) which, if severe enough will trigger cell death via the apoptotic pathway.

Another principal function of the NADPH produced by ER-localized hexose-6-phosphate dehydrogenase is to provide the reducing energy to ER-localized reductases, specifically those involved in steroid hormone metabolism, with 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1; encoded by the HSD11B1 gene) being particularly important. The HSD11B1 gene is located on chromosome 1q32.1 and is composed of 7 exons that generate three alternatively spliced mRNAs all of which encode the same 292 amino acid protein. The primary function of the HSD11B1 encoded enzyme is to reduce the 11-oxo groups (11-oxoreductase activity) in cortisone and 11-dehydrocorticosterone which generates the active glucocorticoids, cortisol and corticosterone, respectively. Although this enzyme can also inactivate (11β-dehydrogenase activity) cortisol and corticosterone by catalyzing the oxidation reactions converting cortisol to cortisone and corticosterone to 11-dehydrocorticosterone, these inactivating reactions are of minimal significance to intracellular glucocorticoid regulation. The primary determinant of the oxo-reductase activity of HSD11B1 is the ratio of NADPH to NADP+ in the ER. Of clinical significance to the role of ER-localized NADPH is that mutations in the H6PD gene are associated with glucocorticoid deficiency.

Humans express a second 11β-hydroxysteroid dehydrogenase encoding gene identified as HSD11B2. Unlike the enzyme encoded by the HSD11B1 gene, the enzyme encoded by the HSDB112 gene possesses only the 11β-dehydrogenase activity. The HSD11B2 gene is located on chromosome 16q22.1 and is composed of 5 exons that encode a 405 amino acid protein. The HSD11B2 gene is expressed primarily in aldosterone-responsive tissues, such as those of the distal tubules of the nephrons of the kidneys. In these tissues the HSD11B2 encoded enzyme is responsible for inactivating cortisol in order to prevent inappropriate activation of the mineralocorticoid receptor (MR). Although the normal receptor for cortisol is the glucocorticoid receptor (GR), the mineralocorticoid receptor has nearly identical affinities for aldosterone (the mineralocorticoid) and cortisol. Mutations in the HSD11B2 gene are associated with an apparent mineralocorticoid excess-induced hypertension due to the lack of ability to inactivate cortisol. As opposed to the use of NADP+ by the HSD11B1 enzyme in the direction of cortisol and corticosterone oxidation, the HSD11B2 enzyme utilizes NAD+ as its cofactor. The expression of the HSD11B2 gene is also found in cells that do not also express the MR such as the placenta. In cells that do not express the MR the function of the HAD11B2 enzyme is to protect those cells from the growth-inhibiting effects of cortisone.

Within adipose tissue and skeletal muscle, both major insulin responsive tissues, the intracellular concentration of glucose-6-phosphate is a direct function of the blood levels of both glucose and insulin. In these tissues insulin action, through its receptor, results in mobilization of GLUT4 transporters to the plasma membrane leading to enhanced glucose uptake from the blood. In the liver, the uptake of glucose, via the GLUT2 transporter, is solely dependent on glucose levels in the blood and given that the Km of GLUT2 for glucose is high (on the order of 15mM), glucose uptake by the liver only occurs, to a significant degree, during the post-feeding period. As the levels of glucose-6-phosphate rise in these tissues there is a concomitant increase in the activities of the ER-localized proteins that are involved in intracellular glucocorticoid activation. These ER-localized proteins include the H6PD and HSD11B1 encoded proteins, as well as the ER membrane-localized glucose-6-phosphate transporter encoded by the G6PT1 gene. The increase in G6PT1, H6PD, and HSD11B1 activities leads to increased conversion of inactive glucocorticoids to their active forms (cortisol and corticosterone). Although glucose consumption directly results in increased intracellular glucocorticoid activation, the consumption of fatty acids will indirectly activate this pathway. Free fatty acids are known to interfere with glucose oxidation via the mechanism first proposed by Philip Randle and co-workers in 1963 and now referred to as the glucose-fatty acid cycle. Briefly, the oxidation of fatty acids leads to increased mitochondrial NADH levels which impair the movement of carbon through the TCA cycle resulting in citrate transport to the cytosol which in turn leads to inhibition of the 6-phosphofructo-1-kinase (PFK1) activity of glycolysis. The increased mitochiondrial NADH level also inhibits the PDHc reaction further impairing the oxidation of glucose. Thus, one of the effects of over eating, either carbohydrate or lipids, particularly within adipose tissue and skeletal muscle, is enhanced glucocorticoid activation.

When the H6PD gene was knocked out in mice the pathology that resulted included fasting hypoglycemia, low hepatic glycogen content, increased sensitivity to insulin, and decreased negative feedback on the hypothalamic-pituitary-adrenal axis. These results strongly implicate an important role for the triad of G6PT1, H6PD, and HSD11b1 in the metabolic modifications that result in response to feeding. Excess nutrient intake, either in the form of carbohydrate or lipid, can result in increased intracellular glucocorticoid activation, especially in adipose tissue and skeletal muscle, both of which are criticasl insulin-responsive tissues. Glucocorticoids have been known for quite a while to induce a state of insulin resistance in both adipose tissue and skeletal muscle. Glucocorticoids interfere with insulin signaling in these tissues resulting in impaired GLUT4 mobilization to the plasma membrane, impaired glucose oxidation, and impaired glycogen synthesis. Within visceral adipose tissue, glucocorticoids stimulate preadipocyte differentiation and triglyceride synthesis. In the liver, glucocorticoids stimulate gluconeogenesis with leads to an exacerbation of the hyperglycemia that is the result of insulin resistance in skeltal muscle and adipose tissue. All of these metabolic disturbances contribute to the development of the metabolic syndrome and the onset of type 2 diabetes

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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 17β-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 Δ4 double bond of testosterone is reduced, by the action of steroid 5α-reductase, producing dihydrotestosterone (DHT). Testosterone and DHT 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 DHT. Dihydrotestosterone 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.

Humans express three different steroid 5α-reductase genes, SRD5A1, SRD5A2, and SRD5A3 where SRD5A2 is the primary enzyme carrying out the testosterone to DHT conversion. The SRD5A1 gene is located on chromosome 5p15.31 and is composed of 7 exons that generate three alternatively spliced mRNAs encoding three distinct isoforms of the enzyme. The SRD5A2 gene is located on chromosome 2p23.1 and is composed of 10 exons that encode a protein of 254 amino acids. Mutations in the SRD5A2 gene are the cause of a form of male pseudohermaphroditism. The SRD5A3 gene is located on chromosome 4q12 and is composed of 6 exons that encode a protein of 318 amino acids. In addition to DHT formation, the SRD5A3 encoded enzyme (also called polyprenol reductase) is required for the conversion of polyprenol to dolichol which is necessary for the synthesis of N-linked glycoproteins. Mutations in the SRD5A3 gene are associated with the development of a particular form of congenital disorder of glycosylation (CDG) identified as CDG-Iq.

Synthesis of the male sex hormones

Synthesis of the male sex hormones in Leydig cells of the testis. P450ssc (CYP11A1), 3β-DH (HSD3B2), and P450c17 (CYP17A1) 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 17β-hydroxysteroid dehydrogenase type 3 (gene symbol HSD17B3). The full name for the primary form of 5α-reductase is 5α-reductase type 2 (gene symbol SRD5A2). Humans express three 5α-reductase genes identified as SRD5A1, SRD5A2, and SRD5A3.

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 female sex hormones

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, human calcitonin has no physiological role in humans but the protein is an important marker for thyroid medullary carcinomas.

Primary Activities of Thyroid Hormone (T3)

Target Tissue Primary Effect Biochemical/Physiological Mechanisms
Adipose tissue catabolic activation of lipolysis and triglyceride breakdown; increases β-adrenergic receptor density
Bone developmental promotes bone growth and differentiation
Central nervous system developmental promotes development of nervous tissue
Gastrointestinal system metabolic increases carbohydrate absorption
Heart both inotropic and chronotropic increases density of β-adrenergic receptors; enhances cardiac responses to catecholamines; enhances ATPase activity of α-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 β-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 150μg/day for adults and 50-200μg/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 Pendred 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. The thyroglobulin gene (symbol: TG) is located on chromosome 8q24.22 and is composed of 52 exons that encode a 2768 amino acid precursor protein. Mutations in the TG gene are associated with thyroid dyshormonogenesis. Functional 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 exocytosed 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 TPO gene is located on chromosome 2p25.3 and is composed of 17 exons that generate six alternatively spliced mRNAs that collectively encode five isoforms of the enzyme. Mutations in the TPO gene are associated with several disorders of thyroid hormone biogenesis which includes congenital hypothyroidism, thyroid hormone organification defect IIA, and congenital goiter.

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 T4 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 thyroid hormones

Structures of the primary thyroid hormones

Mature, iodinated thyroglobulin contains approximately three molecules of T4 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 T4, as well as inactive iodotyrosines and amino acids. T3 and T4 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 T4 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 T4 can be carried in the blood bound to transthyretin (formerly thyroxine-binding prealbumin) or albumin.

The feedback loop that regulates T3 and T4 production is a single short negative loop, with the T3 and T4 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 T4 and the positive effect of TRH.

T3 is the more biologically active thyroid hormone and T4 is converted to T3 within peripheral tissues via the actions of a 5'-deiodinase (thyroxine deiodinase type 1; encoded by the DIO1 gene). 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 NADPH-dependent flavoprotein (iodotyrosine deiodinase; IYD) which recognizes MIT and DIT but not T3 nor T4. The iodine released from MIT and DIT is reused for hormone biogenesis.

Humans express three different thyroid deiodinase genes identified as DIO1, DIO2, and DIO3. Each of these enzymes contains the modified amino acid, selenocysteine. The enzyme encoded by the DIO1 gene, thyroxine deiodinase type I (also called iodothyronine deiodinase type I) is involved in the peripheral tissue conversion of thyroxine (T4) to the more bioactive form, triiodothyronine (T3). In addition to its role in the generation of T3, thyroxine deiodinase I is involved in the catabolism of thyroid hormones. The enzyme encoded by the DIO2 gene, iodothyronine deiodinase type II, is also involved in the conversion of T4 to T3 but does so within the thyroid gland itself. The activity of iodothyronine deiodinase II has been associated with the thyrotoxicosis of Graves disease. The enzyme encoded by the DIO3 gene is involved only in the inactivation (catabolism) of T3 and T4. Expression of the DIO3 gene is highest in the female uterus during pregnancy and in fetal and neonatal tissue suggesting a role for this enzyme in the regulation of thyroid hormone levels and functions during early development. The DIO1 gene is located on chromosome 1p33–p32 and is composed of 4 exons that generate four alternatively spliced mRNAs. The DIO2 gene is located on chromosome 14q24.2–q24.3 and is composed of 6 exons that generate four alternatively spliced mRNAs. The DIO3 gene is located on chromosome 14q32 and is an intronless gene (is a single exon gene) that encodes a protein of 304 amino acids.

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 TRα and TRβ 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 TRα1, TRα2, and TRα3 isoforms from the THRA gene and TRβ1 and TRβ2 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.

Dyshormonogenesis Type Affected Gene / Location Primary Symptoms
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
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 thyroid-stimulating 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 T3 and T4. 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, RARα, RARβ and RARγ. In addition, there is another family of nuclear receptors termed the retinoid X receptors (RXRs) that represents a second class of retinoid-responsive 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: RXRα, RXRβ, and RXRγ 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 co-repressor 1 (NCoR).

model of nuclear receptor (NR) corepressor complex assembly at a target gene

Model for NR interactions with co-repressor: An example of the transcription co-repressor 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.

RXRα is widely expressed with highest levels liver, kidney, spleen, placenta, and skin. The critical role for RXRα in development is demonstrated by the fact that null mice are embryonic lethals. RXRβ is important for spermatogenesis and RXRγ 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-trans-RA) 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: PPARα, PPARβ/δ, and PPARγ. Each of these receptors forms a heterodimer with the RXRs. The first family member identified was PPARα 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 PPARα is the endogenous receptor for polyunsaturated fatty acids. PPARα 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 PPARα 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. PPARγ 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. PPARγ was identified as the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs. The mechanism of action of the TZDs is a function of the activation of PPARγ activity and the consequent activation of adipocytes leading to increased fat storage and secretion of insulin-sensitizing adipocytokines such as adiponectin. PPARδ is expressed in most tissues and is involved in the promotion of mitochondrial fatty acid oxidation, energy consumption, and thermogenesis. PPARδ serves as the receptor for polyunsaturated fatty acids and VLDLs. Current pharmacologic targeting of PPARδ is aimed at increasing HDL levels in humans since experiments in animals have shown that increased PPARδ levels result in increased HDL and reduced levels of serum triglycerides.

Genome wide association screening (GWAS) has demonstrated a role for polymorphisms in the PPARγ 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 PPARγ 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 PPARγ 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 (ERRβ and ERRγ), the retinoid-related orphan receptor (RORα), and the constitutive androstane receptor (CAR).

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Last modified: August 14, 2017