Steroid and Thyroid

Hormones

Srbová Martina

Hormones are chemical messengers that transport

signals from one cell to another

There are 3 major chemical classes of hormones

• steroid hormones - i.e. progesterone

• peptide and protein hormones - i.e. insulin

• amino acid derivatives - epinephrine

Chemical Classification of

Hormones

Classification of Hormones Endocrine hormones: act on cells distant from the site

of their release

Paracrine hormones act only on cells close to the cell

that released them

Autocrine hormones act on the same cell that released

them

Mechanism of Hormone

Action

Peptide hormones and

catecholamines bind

to cell surface

receptors

Steroid and thyroid

hormones act via

intracellular

receptors

All hormone action is receptor mediated

Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

Mechanism of Hormone Action

Regulation of hormone release

Negative feedback

Positive feedback (ovulation, childbirth)

Cyclic changes (cirkadian rythm, our development)

Hormonal cascade

Signal amplification

Environmental or

internal signal

Systemic effects

CNS

Limbic system

Hypothalamus

Anterior pituitary

Target „gland“

Electrical-chemical signal

Electrical-chemical signal

Releasing hormones (ng) - liberins

Anterior pituitary hormone (μg) -tropines

Ultimate hormone (mg)

The gonads, the thyroid gland,

the adrenal cortex

Inhibiting hormones - statins

CNS

Systemic effects

Hormonal cascade

Negative feedback

system

Short feedback

loop

Long feedback

loop

Limbic system

Hypothalamus

Anterior pituitary

Target „gland“

Releasing hormones

Anterior pituitary

hormones

Ultimate hormone

Steroid hormones

Steroids are lipophilic molecules.

All steroids, except calcitriol, have cyclopentanoperhydrophenanthrene structure (sterane).

Structure of Steroid

Hormones

The parental precursor of

steroids - cholesterol

Transport of Hormones

in the Bloodstream Are not water soluble so have to be carried in the blood complexed to

specific binding globulins.

Only the free fraction is biologically active usually less than 10%

• Albumin is non-specific

• Corticosteroid binding globulin

(CBG) - transcortin

• Sex hormone binding globulin

(SHBG)

• Androgen binding protein (ABP)

Carrier-

bound

hormone

Endocrine

cell

Free

hormone

Hormone

Receptor

Hormone

degradation Biological

effects

Hormone half life

Steroids and thyroid hormone, which are bound to plasma proteins, have a long half life

(~ hours)

Peptides and catecholamines are water-soluble, they are transported dissolved in plasma

generally have a very short half life (~ seconds to minutes)

• Because steroid hormones initiate protein synthesis their effects are produced more slowly, but are more long-lasting than those produced by other hormones.

Mechanism of Steroid

Hormone Action

Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

Model of typical steroid hormone receptor

1. Variable domain – interacts with other transcription factors

2. DNA-binding domain – „zinc finger“

3. Domain for dimerization – a site of dimerization of two receptor-hormone complexes

4. Hormone- binding domain

Intracellular receptors

1 2 3 4 H2N- - COOH

„zinc finger structure“

Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

Biosynthesis of Steroid

Hormones

Peptide hormones are encoded by specific genes;

steroid hormones are synthesized from the

enzymatically modified cholesterol.

Thus, there is no gene which encodes steroid

hormone.

The regulation of steroidogenesis involves control of

the enzymes which modify cholesterol into the

steroid hormone.

Hormonal Stimulation of Steroid Hormone

Biosynthesis

• Hormone stimulation depends

on the cell type and receptor

(ACTH for cortisol synthesis,

FSH for estradiol synthesis, LH

for testosterone synthesis etc.)

St AR

StAR – steroidogenic acute regulatory protein

Biosynthesis of Steroid

Hormones

Critical step is the cell activity in mobilizing

cholesterol stored in a droplets, transport of

cholesterol to mitochondria.

The rate-limiting step is the rate of cholesterol side

chain cleavage in mitochondria by enzymes

known as the cytochrome P450 side chain

cleavage enzyme complex.

http://en.wikipedia.org/wiki/Pre

gnenolone

http://chemistry.gravitywaves.com/CHE452/21_Adrenal%20Steroid17.htm

Steroidogenic Enzymes Common name „Old“ name Current name

Cholesteroldesmolase

(Side-chain cleavage enzyme)

P450SCC CYP11A1

3b-hydroxysteroid dehydroge-

nase

3 b-DH 3 b-DH

17a-hydroxylase/17,20 lyase P450C17 CYP17

21-hydroxylase P450C21 CYP21A2

11b-hydroxylase P450C11 CYP11B1

Aldosterone synthase P450C11AS CYP11B2

Aromatase P450aro CYP19

Steroid Hormone Classes

Glucocorticoids

Mineralocorticoids

Progestagens

Androgens

Estrogens

Vitamin D

Steroid hormones

Steroid hormones play important roles in:

- carbohydrate regulation (glucocorticoids)

- mineral balance (mineralocorticoids)

- reproductive functions (gonadal steroids)

Steroids also play roles in inflammatory responses, stress responses, bone metabolism, cardiovascular fitness, behavior, and mood.

Composed of 3 layers (zones):

• outer zone (zona glomerulosa) produces aldosterone (mineralocorticoid)

• middle zone (zona fasciculata) produces cortisol (glucocorticoid)

• inner zone (zona reticularis) produces dehydroepiandrosteron (androgen)

Steroid Hormones of the

Adrenal Cortex

Regulation of Adrenal Steroid

Hormones Synthesis Steroid

hormone

Steroid producing

cells

Signal Second messenger Signal system

Cortisol Zona fasciculata ACTH cAMP, IP3, Ca 2+ Hypothalamic-pituitary

Aldosteron Zona glomerulosa Angiotensin II,III IP3, Ca 2+ Renin-angiotensin

Decreased blood pressure, salt depletion renin

Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin III

angiotensin converting enzyme

aminopeptidase

Renin-angiotensin system

Factors that stimulate renin release

Aldosteron

Na+, H2O resorption

excretion of K+, H+

Transport of Adrenal

Steorid Hormones in the

Bloodstream

CORTISOL

70% is bound to corticosteroid

binding globulin (transcortin)

22% of cortisol is bound to albumin

8% free cortisol

ALDOSTERONE

60% of aldosterone is bound to

albumin

10 % is bound to transcortin

A small amount of aldosterone is

bound to other plasma

proteins

Transcortin is produced in the liver and its synthesis is increased by

estrogens.

Cortisol - effects

proteins

Proteolysis

Amino acids

concentration

in the blood

rises Amino acids

glucose Fatty acids

lipids

lipolysis

Immunosupresive

effect antiinflammatory

effect

bone

degradation

protein synthesis

high

concentration

gluconeogenesis

cortisol

Stress adaptation

Cortisol

Congenital Adrenal Hyperplasia CAH

(adrenogenital syndrome)

Autosomal recessive disease

Insufficient amounts of steroidogenic enzymes – deficiency of end

products, the accumulation of intermediates

21 – hydroxylase deficiency (90% of cases)

cortisol production ACTH – adrenal hyperplasia, androgens

(virilization)

In children with the more severe form of the disorder (mineralocorticoid

deficiency), symptoms often develop 1. – 4. weeks after birth.

Acidosis, hyperkalemia, hyponatremia

Since 2006 newborn screening

Cushing’s syndrome

Glucocorticoid excess

Use of glucocorticoids

Pituitary adenoma, adrenal adenoma

Hyperglycemia - ↑gluconeogenesis

Protein catabolic effects– thinning of the skin, osteoporosis, negative

N balance

Redistribution of fat- buffalo hump

Resistence to infections and inflammatory responses is impaired

Hypernatremia, hypokalemia, hypertension,edema

http://cushingsmoxie.blogspot.cz/2012_04_30_archive.html

Steroid Hormones of the

Gonades

• Hormones that affect the development of the

reproductive organs and sexual characteristics.

Steroid

hormone

Steroid producing

cells

Signal Second

messenger

Signal system

Testosterone Leydig cells LH cAMP Hypothalamic-pituitary

Estradiol Granulosa cells FSH cAMP Hypothalamic-pituitary

Progesterone Corpus luteum LH cAMP Hypothalamic-pituitary

Regulation of Sex Hormones Synthesis

Testes

Leydig cells produce:

• testosteron

Sertoli cells produce:

•dihydrotestosterone (DHT) – but most of conversion of testosterone to DHT occurs outside the testes

• estradiol – a small amount of testosteron is also converted into estradiol by aromatization

– inhibits testosteron synthesis

• inhibin – polypeptide hormone, which inhibits FSH releasing

FSH binds to the Sertoli cells and stimulates the synthesis of androgen-binding protein (ABP). ABP binds testosterone (produced by Leydig cells) and transports it to the site of spermatogenesis

Ovaries

Estradiol is the main hormone produced during the follicular phase of the menstrual cycle. Responsible for maintenance of the female reproductive system and the development of female secondary sex characteristics Estrogens are formed by aromatisation of androgens After ovulation progesterone is made by follicular cells, which now constitute the corpus luteum. Involved in preparing and maintaining the uterus

FOLLICLE OVULATION CORPUS LUTEUM

Uterine endometrium Menstruation

Follicular phase Luteal phase

Menstrual cycle

Transport of Sex Hormones in

the Bloodstream Testosterone & estradiol bind to sex hormone binding globulin (SHBG). Affinity of SHBG for testosterone is higher than for estradiol

.

Progesterone binds to transcortin.

• Before puberty - the level of SHBG is about the same in males and females .

• At the puberty - there is a small decrease in the level of circulating SHBG in females and larger decrease in males, insuring relatively greater amount of the unbound, biologically active sex hormones.

• In adults, males have half of the amount of SHBG than females.

• Testosterone lowers SHBG levels in blood, whereas estradiol raises SHBG levels.

HO

Vitamin D3

cholecalciferol

Diet

HO

OH

25(OH) D3

Liver

25-hydroxylase

OH HO

OH

1,25(OH)2 D3 (active hormone form)

Kidney

1α- hydroxylase

HO 7

7-dehydrocholesterol

UV from

sunlight Skin

Calcitriol - 1,25 (OH)2-D3

1a-hydroxylation is the rate-limiting step in calcitriol synthesis

Calcitriol

- increases uptake of Ca2+ and phosphate from the intestine

- stimulates calcium binding protein synthesis

- increases reabsorption of Ca2+ by the kidney

Regulation of 1a-hydroxylase

Activation Inhibition

Hypocalcemia

Parathroid hormone

Hypophosphatemia

Calcitriol

Calcitriol - 1,25 (OH)2-D3

Hormone Catabolism and

Excretion

• Inactivation of steroids involves reductions and conjugation to glucuronides or sulfate to increase their water solubility.

• Most are catabolized by the liver and kidneys.

• 70% of the conjugated steroids are excreted in the urine, 20 % leave in feces and rest exit through the skin.

3

estron-3sulfate

Thyroid Hormones

3,5,3´-triiodothyronine (T3)

Thyroxine (T4)

3,5,3´,5´-tetraiodothyronine

Thyroid Hormones

Biosynthesis of thyroxine • The main synthetized thyroid hormone is thyroxine, but

triiodothyronine is tentimes more potent

• Precursor molecule for synthesis thyroid hormones is tyrosine derivative

• Biosynthesis is perfomed on tyrosine residues bound in protein of thyroid gland – thyreoglobulin

• The first step is transport of iodide into follicle cells of thyroid gland

• Active transport of iodide into the follicle cell is mediated iodide pump (the concentration outside is 25times lower than inside)

Transport of thyroid

hormones by blood

The main transporting protein is thyroxine binding globulin (TBG). Its

affinity for T4 is 10 times higher than for T3 .

The further proteins, binding thyroid hormones, are thyroxine binding

prealbumin and albumin.

More than 99% of T4 is bound on plasma proteins.

Control of thyroid hormone

synthesis and secretion

Pituitary hormone thyreotropin (TSH)

upregulates activity of iodide pump of

follicle cells of thyroid gland

Endocytosis of iodinated

thyreoglobulin and following secretion

of T3 and T4 is also upregulated by

TSH

Production of TSH is upregulated by

TRH and controled by thyroid

hormones via negative feedback

Thyroid Hormones

Bind to intracellular receptor, increase expression of numerous metabolic

enzyme

Stimulate metabolism and influence development and maturation

stimulate the consumption of oxygen

increase metabolic rate

regulate thermogenesis

Hyperthyroidism, excessive secretion of thyroid hormones, causes

high body temperature, weight loss, irritability, and

high blood pressure

Hypothyroidism, low secretion of thyroid hormones, causes weight

gain, lethargy, and intolerance to cold

during fetal and immediate postnatal periods results

in irreversible physical and metal retardation cretinism

Degradation of thyroid hormones

Deiodation

Oxidative deamination

Conjugation with glucuronate, sulfate

Literature

Devlin, T. M. Textbook of biochemistry: with clinical correlations. 6th edition.

Wiley-Liss, 2006.

Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009

(M. Lieberman, A.D. Marks)

Color Atlas of Biochemistry, second edition, 2005 (J. Koolman and K.H.

Roehm)