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D. Mode of action of steroid hormones

 

 

 

Steroid

 

 

 

hormone (H)

 

 

 

ECF

 

 

 

Cell

 

 

III

 

 

Transmission

Cytoplasmic

 

 

receptor (R)

 

 

HSP

 

H-R

 

complex

Signal

 

 

Amino acids

 

Trans-

(AA)

 

location

ATP

tRNA

DNA

Cellular

 

 

 

AA-tRNA

rRNA

 

 

 

 

 

 

Translation

 

Transcription

11.7

 

 

 

 

mRNA

Cell

Plate

 

nucleus

Ribosome

 

 

 

 

Induced

Cell response

 

protein

 

 

 

 

E. Nitric oxide (NO) as a transmitter substance

 

Messenger,

 

 

 

 

 

 

e.g., acetylcholine

 

 

 

 

Ca2+

 

 

 

 

 

 

 

channel

 

 

Receptor

 

 

 

Cell

 

 

 

 

 

membrane

 

 

 

 

 

 

Go Open

Vaso-

 

 

Gq

 

DAG

 

dilatation

 

 

 

β

IP3

Ca2+

Calmodulin

[Ca2+]

 

 

 

PLC-

 

 

 

 

 

PIP2

 

 

 

 

 

 

 

 

Ca2+

 

 

?

 

 

 

 

 

 

 

 

 

 

stores

 

Ca2+-

 

 

 

 

 

 

Protein

 

 

 

 

 

 

calmodulin

 

 

 

 

 

 

complex

kinase G

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Diffusion

 

 

 

 

 

Activated

Activated

 

 

 

 

NO synthase

 

GTP

 

 

 

NO

Arginine

 

 

 

 

 

 

 

 

 

Cytosolic

 

 

 

 

O2,NADPH

guanylate

 

 

 

 

 

 

cyclase

 

 

 

 

Citrulline

 

cGMP

 

 

 

 

Cell 1

 

279

Cell 2

ECF

 

 

 

 

 

(e.g., endothelial cell)

 

(e.g., vascular myocyte)

 

 

 

 

 

 

 

 

 

Despopoulos, Color Atlas of Physiology © 2003 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Hypothalamic–Pituitary System

In the hypothalamus, (1) humoral signals from the periphery (e.g., from circulating cortisol) can be converted to efferent neuronal signals, and (2) afferent neuronal signals can be converted to endocrine messengers (neurosecretion).

 

The first case is possible because the hypothalamus is

Reproduction

situated near circumventricular organs like the or-

ganum vasculosum laminae terminalis (OVLT), sub-

 

 

fornical organ, the median eminence of the hypo-

 

thalamus, and the neurohypophysis. Since there is

 

no blood-brain barrier there, hydrophilic peptide

and

hormones can also enter.

 

 

The hypothalamus is closely connected to

 

Hormones

other parts of the CNS (!p. 330). It controls

sleeping-waking rhythm (!p. 334) and to

 

many autonomous regulatory functions and

 

its neuropeptides influence higher brain func-

 

tions. The hypothalamus is related to the

11

psychogenic factors. Stress,

for

example,

stimulates the release of cortisol (via CRH,

 

 

ACTH) and can lead to the cessation of hor-

 

mone-controlled menstruation (amenorrhea).

 

Neurosecretion.

Hypothalamic

neurons

 

synthesize hormones, incorporate them in

 

granules that are transported to the ends of the

 

axons (axoplasmic

transport

!p. 42), and

 

secrete them into the bloodstream. In this way,

 

oxytocin and ADH are carried from magno-

 

cellular hypothalamic nuclei to the neurohy-

 

pophysis, and RHs and IHs (and ADH) reach the

 

median eminence of the hypothalamus (!A).

 

The action potential-triggered exocytotic re-

 

lease of the hormones into the bloodstream re-

 

sults in Ca2+ influx

into the

nerve

endings

 

(!p. 50ff.).

 

 

 

Oxytocin (Ocytocin) and antidiuretic hormone (ADH) are two posterior pituitary hormones that enter the systemic circulation directly. ADH induces water retention in the renal collecting ducts (V2-rec.; !p. 166) and induces vasoconstriction (endothelial V1 rec.) by stimulating the secretion of endothelin-1 (!p. 212ff.). ADH-bearing neurons also secrete ADH into the portal venous circulation (see below). The ADH and CRH molecules regulate the secretion of ACTH by the adenohy-

280pophysis. Oxytocin promotes uterine contractions and milk ejection (!p. 304). In nursing

mothers, suckling stimulates nerve endings in the nipples, triggering the secretion of oxytocin (and prolactin, !p. 303) via neurohumoral reflexes.

Releasing hormones (RH) or liberins that stimulate hormone release from the adenohypophysis (Gn-RH, TRH, SRH, CRH; !p. 270ff.) are secreted by hypothalamic neurons into a kind of portal venous system and travel only a short distance to the anterior lobe (!A). Once in its vascular network, they trigger the release of anterior pituitary hormones into the systemic circulation (!A). Some anterior pituitary hormones are regulated by release-inhib- iting hormones (IH) or statins, such as SIH and PIH = dopamine (!p. 270ff.). Peripheral hormones, ADH (see above) and various neurotransmitters such as neuropeptide Y (NPY), norepinephrine (NE), dopamine, VIP and opioids also help to regulate anterior pituitary functions (!p. 272).

The four glandotropic hormones (ACTH, TSH, FSH and LH) and the aglandotropic hormones (prolactin and GH) are secreted from the anterior pituitary (!A). The secretion of growth hormone (GH = somatotropic hormone, STH) is subject to control by GH-RH, SIH and IGF-1. GH stimulates protein synthesis (anabolic action) and skeletal growth with the aid of somatomedins (growth factors formed in the liver), which play a role in sulfate uptake by cartilage. Somatomedin C = insulin-like growth factor-1 (IGF-1) inhibits the release of GH by the anterior pituitary via negative feedback control. GH has lipolytic and glycogenolytic actions that are independent of somatomedin activity.

Proopiomelanocortin (POMC) is a peptide precursor not only of ACTH, but (inside or outside the anterior pituitary) also of !-endorphin and α-melano- cyte-stimulating hormone (α-MSH = α-melanocor- tin). !-endorphin has analgesic effects in the CNS and immunomodulatory effects, while α-MSH in the hypothalamus helps to regulate the body weight (!p. 230) and stimulates peripheral melanocytes.

Despopoulos, Color Atlas of Physiology © 2003 Thieme

All rights reserved. Usage subject to terms and conditions of license.

A. Hypothalamic-pituitary hormone secretion (schematic)

Nucleus

Hypothalamus

ventromedialis

 

Nucleus

Nucleus

dorsomedialis

supraopticus

Nucleus

Nucleus

infundibularis

paraventricularis

 

RH, IH

 

 

ADH

Chiasma

Oxytocin

 

opticum

Corpus

 

 

mamillare

Superior hypophysial artery

Axoplasmic transport by neurosecretory nerve cells

Release of RHs, IHs, ADH, NE, NPY and

other transmitters

Portal veins

Inferior hypo-

physial artery

RH induce release of

RH, IH,

ADH

anterior pituitary hormones

IH inhibit their release

 

 

 

 

Release of

 

 

 

 

ADH, oxytocin

 

 

 

Pituitary

 

 

 

 

veins

Posterior pituitary

 

 

 

 

 

 

 

 

(neurohypophysis)

Anterior pituitary

Anterior pituitary

Posterior pituitary

(adenohypophysis)

 

hormones

hormones

 

 

 

ADH, oxytocin

 

ACTH

PRL

 

 

 

 

 

STH

LH

 

 

 

TSH

α-MSH

 

 

 

FSH

β-endorphin

 

RH =Releasing hormones

 

 

 

 

 

 

 

 

IH = (Release-)Inhibiting hormones

Plate 11.8 Hypothalamic–Pituitary System

281

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Carbohydrate Metabolism and

glucose concentration as constant as possible

 

(!A); and (4) promote growth.

 

 

 

Pancreatic Hormones

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Glucose is the central energy carrier of the

Insulin

 

 

 

 

 

 

 

human metabolism. The brain and red blood

Synthesis. Insulin is a 6 kDa peptide (51 amino acids,

 

cells are fully glucose-dependent. The plasma

AA) formed by the C chain cleaved from proinsulin

 

glucose concentration (blood sugar level) is

(84 AA), the precursor of which is preproinsulin, a pre-

 

determined by the level of glucose production

prohormone. Insulin contains two peptide chains (A

 

and B) held together by disulfide bridges Degrada-

 

and consumption.

 

 

 

tion: Insulin has a half-life of about 5–8 min and is de-

 

 

 

 

Reproduction

The following terms are important for proper under-

graded mainly in liver and kidneys.

 

 

standing of carbohydrate metabolism (!A, C):

Secretion.

Insulin

is

secreted in pulsatile

 

 

1. Glycolysis generally refers to

the anaerobic

 

bursts, mainly in response to increases in the

 

conversion of glucose to lactate (!p. 72). This oc-

 

blood levels of glucose (!B right), as fol-

 

curs in the red blood cells, renal medulla, and skeletal

 

muscles (!p. 72). Aerobic oxidation of glucose oc-

lows: plasma glucose "!glucose in B cells

and

curs in the CNS, heart, skeletal muscle and in most

"!glucose oxidation "!cytosolic ATP

other organs.

 

 

"!closure

of

ATP-gated K+

channels

Hormones

2. Glycogenesis, i.e., the synthesis of glycogen

!depolarization !opening of voltage-gated

muscle can only be used by that muscle.

and (b) re-opening of K+ channels (deactivated

 

from glucose (in liver and muscle), facilitates the

Ca2+

channels

!cytosolic Ca2+". The rising

 

storage of glucose and helps to maintain a constant

Ca2+ in B cells leads to (a) exocytosis of insulin

 

plasma glucose concentration. Glycogen stored in a

 

 

 

 

 

 

 

 

 

11

3. Glycogenolysis is the breakdown of glycogen

by

feedback

control).

Stimulation.

Insulin

to glucose, i.e., the opposite of glycogenesis.

secretion is stimulated mainly during food

 

 

4. Gluconeogenesis is the production of glucose

digestion via acetylcholine (vagus nerve),

 

(in liver and renal cortex) from non-sugar molecules

gastrin, secretin,

GIP

(!p. 234)

and

GLP-1

 

such as amino acids (e.g., glutamine), lactate (pro-

(glucagon-like

peptide

= enteroglucagon), a

 

duced by anaerobic glycolysis in muscles and red

 

peptide that dissociates from intestinal pro-

 

cells), and glycerol (from lipolysis).

 

 

 

glucagon. Certain amino acids (especially ar-

 

5. Lipolysis is the breakdown of triacylglycerols

 

ginine and leucine), free fatty acids, many

 

into glycerol and free fatty acids.

 

 

6. Lipogenesis is the synthesis of triacylglycerols

pituitary hormones and some steroid hor-

 

(for storage in fat depots).

 

mones also increase insulin secretion. Inhibi-

 

Islets of Langerhans in the pancreas play a pri-

tion. Epinephrine

and

norepinephrine (α2-

 

adrenoceptors; !A, B), SIH (!p. 273 B) and

 

mary role in carbohydrate metabolism. Three

 

the neuropeptide galanin inhibit insulin secre-

 

cell types (A, B, D) have been identified so far

 

tion. When hypoglycemia occurs due, e.g., to

 

(!p. 273 B). 25% of all islet cells are type A (α)

 

fasting or prolonged physical exercise, the low

 

cells that produce glucagon, 60% are B (") cells

 

blood glucose concentration is sensed by cen-

 

that synthesize insulin, and 10% are D (δ) cells

 

tral chemosensors for glucose, leading to reflex

 

that secrete

somatostatin (SIH). These hor-

 

activation of the sympathetic nervous system.

 

mones mutually influence the synthesis and

 

 

 

 

 

 

 

 

 

 

secretion of each other (!p. 273 B). Islet cells

The insulin receptor is a heterotetramer (α2"2) con-

 

in the pancreas head synthesize pancreatic

sisting of two extracellular α subunits and two trans-

 

polypeptide,

the physiological

function of

membranous " subunits. The α subunits bind the

 

which is not yet clear. High concentrations of

hormone. Once the " subunits are autophosphory-

 

lated, they

act

as

receptor tyrosine

kinases that

 

these hormones reach the liver by way of the

 

phosphorylate insulin receptor substrate-1 (IRS-1). In-

 

portal venous circulation.

 

 

 

tracellular proteins with SH2 domains are phospho-

 

Function. Pancreatic hormones (1) ensure

 

rylated by IRS-1 and pass on the signal (!p. 277 C3).

 

that ingested food is stored as glycogen and fat

Action of insulin (!A, B, C). Insulin has ana-

 

(insulin); (2) mobilize energy reserves in re-

 

bolic and lipogenic effects, and promotes the

 

sponse to food deprivation, physical activity or

 

storage of glucose, especially in the liver, where

282

stress (glucagon and the non-pancreatic hor-

it activates enzymes that promote glycolysis

mone epinephrine); (3) maintain the plasma

 

 

 

!

Despopoulos, Color Atlas of Physiology © 2003 Thieme

All rights reserved. Usage subject to terms and conditions of license.

A. Glucose metabolism (simplified overview)

Food

 

g/L

mmol/L

1.8

10

Blood glucose

 

0.8

4.5

Red cell

Glucose

in urine Anaerobic glycolysis

liver

by liver

 

Glucose released from

Glucose taken up

Lactate

 

 

 

Lactate

 

 

Glucose

 

Muscle

 

 

 

 

 

 

 

 

Glycogen

 

Glucose

 

E

 

 

 

taken up

 

 

 

 

 

 

 

 

 

E

by cell

 

 

 

 

 

 

 

 

 

 

 

Ι

 

 

 

 

Ι

 

 

 

 

Glucose

 

CNS

 

 

Ι

 

Ι

 

Oxidation

 

 

Anaerobic glycolysis

Oxidation (aerobic)

 

(aerobic)in CNS

Energy

 

 

 

Energy

 

 

 

 

 

 

Lactate

 

CO2 + H2O

CO2 + H2O

 

 

 

 

 

 

 

 

 

 

Proteins

 

To liver

 

G

 

 

 

C

 

 

 

 

 

 

Gluconeogenesis

 

 

 

 

 

 

G

 

Amino

Ι

 

 

 

 

 

 

acids

Glycogenolysis

Ι C

Glycerol

 

 

 

 

 

 

 

Lipolysis

 

 

 

 

 

 

Ι

C

 

 

 

Glycogenesis

G

E

G

 

 

Lipogenesis

 

E

 

 

 

 

Triacyl-

 

 

 

Free

 

 

Glycogen

Fat tissue

glycerol

Liver

fatty acids

 

(fat)

 

 

 

Stimulated by:

 

 

 

Ketogenesis

 

 

 

 

 

 

 

Ι

Insulin

 

 

 

 

 

(after meals)

C

Cortisol

 

 

 

 

Epinephrine

 

Glucagon

 

 

 

E (exercise, etc.)

G

(hunger)

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Plate 11.9 Carbohydrate Metabolism I

283

 

!

 

and glycogenesis and suppresses those involved

 

in gluconeogenesis. Insulin also increases the

 

number of GLUT-4 uniporters in skeletal myo-

 

cytes. All these actions serve to lower the

 

plasma glucose concentration (which in-

 

creases after food ingestion). About two-thirds

 

of the glucose absorbed by the intestines after

 

a meal (postprandial) is temporarily stored

 

and kept ready for mobilization (via glucagon)

Reproduction

during the interdigestive phase. This provides

a relatively constant supply of glucose for the

 

 

glucose-dependent CNS and vital organs in ab-

 

sence of food ingestion. Insulin increases the

 

storage of amino acids (AA) in the form of pro-

 

teins, especially in the skeletal muscles (ana-

and

bolism). In addition, it promotes growth, inhib-

its extrahepatic lipolysis (!p. 257, D) and af-

Hormones

(35 mg/dL) produce glucose deficiencies in the brain,

 

fects K+ distribution (!p. 180).

 

Hypoglycemia develops when the insulin concentra-

 

tion is too high. Glucose levels of !2 mmol/L

11

which can lead to coma and hypoglycemic shock.

The excessive intake of carbohydrates can over-

 

 

load glycogen stores. The liver therefore starts to

 

convert glucose into fatty acids, which are trans-

 

ported to and stored in fatty tissues in the form of tri-

 

 

acylglycerols (!p. 257 D).

 

Diabetes mellitus (DM). One type of DM is in-

 

sulin-dependent diabetes mellitus (IDDM), or type 1

 

DM, which is caused by an insulin deficiency. Another

 

type is non-insulin-dependent DM (NIDDM), or type 2

 

DM, which is caused by the decreased efficacy of in-

 

sulin and sometimes occurs even in conjunction with

 

increased insulin concentrations. DM is characterized

 

by an abnormally high plasma glucose concentration

 

(hyperglycemia), which leads to glucosuria (!p. 158).

 

Large quantities of fatty acids are liberated since

 

lipolysis is no longer inhibited (!p. 257 D). The fatty

 

acids can be used to produce energy via acetyl-

 

coenzyme A (acetyl-CoA); however, this leads to the

 

formation of acetoacetic acid, acetone (ketosis), and

 

!-oxybutyric acid (metabolic acidosis, !p. 142). Be-

 

cause hepatic fat synthesis is insulin-independent

 

and since so many fatty acids are available, the liver

 

begins to store triacylglycerols, resulting in the

 

development of fatty liver.

 

Glucagon, Somatostatin and Somatotropin

 

Glucagon released from A cells is a peptide

 

hormone (29 AA) derived from proglucagon

 

(glicentin). The granules in which glucagon is

 

stored are secreted by exocytosis. Secretion is

284stimulated by AA from digested proteins (especially alanine and arginine) as well as by hy-

poglycemia (e.g., due to fasting, prolonged physical exercise; !B) and sympathetic impulses (via !2 adrenoceptors; !A). Glucagon secretion is inhibited by glucose and SIH (!p. 273, B) as well as by high plasma concentrations of free fatty acids.

The actions of glucagon (!A, B, C) (via cAMP; !p. 274) mainly antagonize those of insulin. Glucagon maintains a normal blood glucose level between meals and during phases of increased glucose consumption to ensure a constant energy supply. It does this (a) by increasing glycogenolysis (in liver not muscle) and (b) by stimulating gluconeogenesis from lactate, AA (protein degradation = catabolism) and glycerol (from lipolysis).

Increased plasma concentrations of amino acids (AA) stimulate insulin secretion which would lead to hypoglycemia without the simultaneous ingestion of glucose. Hypoglycemia normally does not occur, however, since AA also stimulate the release of glucagon, which increases the blood glucose concentration. Glucagon also stimulates gluconeogenesis from AA, so some of the AA are used for energy production. In order to increase protein levels in patients, glucose must therefore be administered simultaneously with therapeutic doses of AA to prevent their metabolic degradation.

Somatostatin (SIH). Like insulin, SIH stored in D cells (SIH 14 has 14 AA) is released in response to increased plasma concentrations of glucose and arginine (i.e., after a meal). Through paracrine pathways (via Gi-linked receptors), SIH inhibits the release of insulin (!p. 273, B). Therefore, SIH inhibits not only the release of gastrin, which promotes digestion (!p. 243, B3), but also interrupts the in- sulin-related storage of nutrients. SIH also inhibits glucagon secretion (!p. 273 B). This effect does not occur in the presence of a glucose deficiency because of the release of catecholamines that decrease SIH secretion.

Somatotropin (STH) = growth hormone (GH). The short-term effects of GH are similar to those of insulin; its action is mediated by somatomedins (!p. 280). In the long-term, GH increases the blood glucose concentration and promotes growth.

The effects of glucocorticoids on carbohydrate metabolism are illustrated on plate C and explained on p. 296.

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B. Hormonal control of blood glucose concentration

 

 

 

 

Blood glucose drops

 

 

Blood glucose rises

 

 

below normal

 

 

above normal level

 

 

 

 

5mmol/L

 

 

 

5mmol/L

 

 

 

 

 

 

 

 

 

II

 

Pancreas

 

 

 

 

 

Metabolism

 

B

 

 

 

 

B

 

A

cells

 

Adrenal

 

A

cells

 

cells

 

 

 

cells

 

 

rec.

 

 

 

 

Carbohydrate

 

 

medulla

 

 

 

 

rec.

 

 

 

 

 

 

2

 

 

 

 

 

 

2

α

 

Hypothalamus

 

 

 

β

Epi-

 

 

Epi-

 

 

 

 

nephrine

 

 

 

nephrine

 

 

 

 

 

 

 

 

 

 

 

 

 

 

11.10

 

 

 

ACTH

 

 

 

ACTH

Plate

 

 

 

 

 

 

 

 

 

 

 

STH

 

 

 

STH

 

Adrenal cortex

long-term

 

 

 

short-term

Glucagon

Insulin

 

Cortisol

Glucagon

Insulin

Cortisol

 

 

 

 

 

 

 

Stimulates

 

 

 

 

 

 

 

 

Inhibits

 

 

 

 

 

 

 

 

No stimulation

 

 

Blood glucose returns to normal

 

 

No inhibition

 

 

 

 

 

 

 

 

C. Hormonal effects on carbohydrate and fat metabolism

 

 

 

Hormone

Insulin

 

Glucagon

Epinephrine

Cortisol

 

Glucose

Function

Satiated

 

 

Buffer

 

 

 

Hungry

Stress, exercise

 

Supply

 

 

 

 

 

 

 

 

 

 

 

 

Muscle,

 

 

 

 

 

 

 

 

 

 

 

 

 

Muscle,

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uptake by cell

 

 

 

 

 

 

fat

 

 

 

 

 

 

 

 

Muscle

 

 

 

 

fat

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Glycolysis

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Gluconeogenesis (liver)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Glycogen

 

 

 

Liver,

 

Liver

 

Liver,

 

 

 

Liver

 

Synthesis

 

 

 

Lysis

 

muscle

 

 

 

 

 

 

 

 

muscle

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fat

 

 

 

Liver,

 

 

Fat

 

Fat

 

Fat

285

Synthesis

 

 

 

Lysis

 

fat

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Thyroid Hormones

thyrocolloid. The phenol ring of one DIT (or

 

MIT) molecule links with another DIT

 

 

 

The thyroid gland contains spherical follicles

molecule (ether bridges). The resulting thyro-

 

(50–500 µm in diameter). Follicle cells synthe-

globulin chain now contains tetraiodothy-

 

size the two iodine-containing thyroid hor-

ronine residues and (less) triiodothyronine resi-

 

mones thyroxine (T4, tetraiodothyronine) and

dues (!C). These are the storage form of T4 and

 

triiodothyronine (T3). T3 and T4 are bound to

T3.

 

the glycoprotein thyroglobulin (!B2) and

TSH also stimulates T3 and T4 secretion. The

 

stored in the colloid of the follicles (!A1, B1).

iodinated thyroglobulin in thyrocolloid are re-

Reproduction

The synthesis and release of T3/T4 is controlled

absorbed by the cells via endocytosis (!B3,

by the thyroliberin (= thyrotropin-releasing

C). The endosomes fuse with primary lyso-

 

 

hormone, TRH)—thyrotropin (TSH) axis (!A,

somes to form phagolysosomes in which thy-

 

and p. 270ff.). T3 and T4 influence physical

roglobulin is hydrolyzed by proteases. This

 

growth, maturation and metabolism. The par-

leads to the release of T3 and T4 (ca. 0.2 and

 

afollicular cells (C cells) of the thyroid gland

1–3 mol per mol of thyroglobulin, respec-

and

synthesize calcitonin (!p. 292).

tively). T3 and T4 are then secreted into the

Thyroglobulin, a dimeric glycoprotein (660 kDa) is

bloodstream (!B3). With the aid of deiodase,

Hormones

I– meanwhile is split from concomitantly re-

synthesized in the thyroid cells. TSH stimulates the

 

 

leased MIT and DIT and becomes reavailable

 

transcription of the thyroglobulin gene. Thyro-

 

for synthesis.

 

globulin is stored in vesicles and released into the col-

 

loid by exocytosis (!B1 and p. 30).

Control of T3/T4 secretion. TSH secretion by

11

Iodine uptake. The iodine needed for hormone

the anterior pituitary is stimulated by TRH, a

hypothalamic tripeptide (!p. 280) and in-

 

synthesis is taken up from the bloodstream as

 

hibited by somatostatin (SIH) (!A and p. 270).

 

iodide (I–). It enters thyroid cells through sec-

 

The effect of TRH is modified by T4 in the

 

ondary active transport by the Na+-I– symport

 

plasma. As observed with other target cells,

 

carrier (NIS) and is concentrated in the cell ca.

 

the T4 taken up by the thyrotropic cells of the

 

25 times as compared to the plasma (!B2).

 

anterior pituitary is converted to T3 by 5!-deio-

 

Via cAMP, TSH increases the transport capacity

 

dase. T3 reduces the density of TRH receptors in

 

of basolateral I– uptake up to 250 times. Other

 

the pituitary gland and inhibits TRH secretion

 

anions competitively inhibit I– uptake; e.g.,

 

by the hypothalamus. The secretion of TSH and

 

ClO4–, SCN– and NO2–.

 

consequently of T3 and T4 therefore decreases

 

Hormone synthesis. I– ions are continuously

 

(negative feedback circuit). In neonates, cold

 

transported from the intracellular I– pool to the

 

seems to stimulate the release of TRH via neu-

 

apical (colloidal) side of the cell by a I–/Cl– anti-

 

ronal pathways (thermoregulation, !p. 224).

 

porter, called pendrin, which is stimulated by

 

TSH is a heterodimer (26 kDa) consisting of an

 

TSH. With the aid of thyroid peroxidase (TPO)

 

α subunit (identical to that of LH and FSH) and

 

and an H2O2 generator, they are oxidized to el-

 

a " subunit. TSH controls all thyroid gland func-

 

ementary I20 along the microvilli on the colloid

 

tions, including the uptake of I–, the synthesis

 

side of the cell membrane. With the help of

 

and secretion of T3 and T4 (!A-C), the blood

 

TPO, the I0 reacts with about 20 of the 144 ty-

 

flow and growth of the thyroid gland.

 

rosyl residues of thyroglobulin (!C). The

 

 

 

phenol ring of the tyrosyl residue is thereby

Goiter (struma) is characterized by diffuse or nodu-

 

iodinated at the 3 and/or 5 position, yielding a

lar enlargement of the thyroid gland. Diffuse goiter

 

protein chain containing either diiodotyrosine

can occur due to an iodine deficiency, resulting in

 

(DIT) residues and/or monoiodotyrosine (MIT)

T3/T4 deficits that ultimately lead to increased secre-

 

tion of TSH. Chronic elevation of TSH leads to the

 

residues. These steps of synthesis are stimu-

 

proliferation of follicle cells, resulting in goiter

 

lated by TSH (via IP3) and inhibited by

 

development (hyperplastic goiter). This prompts an

 

thiouracil, thiocyanate, glutathione, and other

 

increase in T3/T4 synthesis, which sometimes nor-

 

reducing substances. The structure of the thy-

malizes the plasma concentrations of T3/T4 (euthyroid

286

roglobulin molecule allows the iodinated ty-

goiter). This type of goiter often persists even after

 

rosyl residues to react with each other in the

the iodide deficiency is rectified.

 

 

!

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A. Thyroid hormones (overview)

 

 

 

SIH

TRH

 

 

Thyrocytes

T4

Thyroxin

 

HVL

 

(tetraiodothyronine)

 

Capillaries

 

5’-Deiodase

 

TSH

 

 

 

 

Thyroid gland

Colloid

 

T3 Triiodothyronine

 

 

 

Iodine uptake,

 

 

 

hormone synthesis

 

 

 

and secretion

Metabolism, growth, maturation, etc.

 

(See B.)

B. Hormone synthesis and secretion

1 Thyroglobulin synthesis

 

Thyroglobulin vesicle

 

Amino

 

 

 

Carbohydrates

 

 

 

acids

 

 

 

 

 

 

 

Thyroglobulin

 

Peptides

 

 

 

 

 

 

 

Exocytosis

 

Ribosomes

 

 

 

Endoplasmic

 

Golgi apparatus

 

 

 

 

 

Capillary

reticulum

Thyroid cell (thyrocyte)

Colloid

 

2 Iodine uptake, hormone synthesis and storage

 

SCN–

 

 

Thyroid

 

CIO4–

 

 

peroxidase

 

NO2–

 

I– pool

T3/T4 synthesis

T4 T3

 

 

I–

 

 

(see C.)

 

Na+ symport

 

 

 

 

NIS Na+

 

TSH

 

TSH

 

 

T3/T4 storage

 

 

 

 

 

 

 

(bound to thyroglobulin)

3 Hormone secretion

Primary lysosomes

TSH

with proteases

 

 

 

Endocytosis

T4

T3

 

Fusion

 

 

 

 

 

 

 

Thyroglobulin

I–

 

 

cleavage

Deiodase

 

 

 

 

 

 

MIT, DIT

Plate 11.11 Thyroid Hormones I

287

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11 Hormones and Reproduction

288

!

Hypothyroidism occurs when TSH-driven thyroid enlargement is no longer able to compensate for the T3/T4 deficiency (hypothyroid goiter). This type of goiter can also occur due to a congenital disturbance of T3/T4 synthesis (see below) or thyroid inflammation. Hyperthyroidism occurs when a thyroid tumor (hot node) or diffuse struma (e.g., in Grave’s disease) results in the overproduction of T3/T4, independent of TSH. In the latter case, an autoantibody against the TSH receptor binds to the TSH receptor. Its effects mimic those of TSH, i.e., it stimulates T3/T4 synthesis and secretion.

T3/T4 transport. T3 and T4 occur at a ratio of 1 : 40 in the plasma, where !99% of them (mainly T4) are bound to plasma proteins: thy- roxine-binding globulin (TBG), thyroxine-bind- ing prealbumin (TBPA), and serum albumin. TBG transports two-thirds of the T4 in the blood, while TBPA and serum albumin transport the rest. Less than 0.3% of the total T3/T4 in blood occurs in an unbound (free) form, although only the unbound molecules have an effect on the target cells. Certain drugs split T3 and T4 from protein bonds, resulting in increased plasma concentrations of the free hormones.

Potency of T3/T4. T3 is 3–8 times more potent than T4 and acts more rapidly (half-life of T3 is 1 day, that of T4 7 days). Only ca. 20% of all circulating T3 originate from the thyroid; the other 80% are produced by the liver, kidneys, and other target cells that cleave iodide from T4. The conversion of T4 to T3 is catalyzed by microsomal 5!-deiodase, which removes iodine from the 5! position on the outer ring (!D). T3 is therefore the more potent hormone, while T4 is mainly ascribed a storage function in plasma.

The inactive form of T3 called reverse T3 (rT3) is produced from T4 when the iodine is split from the inner ring with the aid of a 5- (not 5!-)deiodase. Approximately equal amounts of T3 and rT3 are normally produced in the periphery (ca. 25 µg/day). When a person fasts, the resulting inhibition of 5!-deiodase decreases T3 synthesis (to save energy, see below) while rT3 synthesis increases. Pituitary 5!-deiodase is not inhibited, so TSH secretion (unwanted in this case) is suppressed by the negative feedback.

T3/T4 receptors are hormone-sensitive transcription factors located in the cell nuclei. Hor- mone–receptor complexes bind to regulator

proteins of certain genes in the nuclei and influence their transcription.

The actions of T3/T4 are numerous and mainly involve the intermediate metabolism. The thyroid hormones increase the number of mitochondria and its cristae, increase Na+-K+- ATPase activity and modulate the cholesterol metabolism. This results in an increase in energy turnover and a corresponding rise in O2 consumption and heat production. T3 also specifically stimulates heat production by increasing the expression of the uncoupling protein thermogenin in brown fat (!p. 222). T3 also influences the efficacy of other hormones. Insulin, glucagon, GH and epinephrine lose their energy turnover-increasing effect in hypothyroidism, whereas the sensitivity to epinephrine increases (heart rate increases, etc.) in hyperthyroidism. T3 is thought to increase the density of !-adrenoceptors. T3 also stimulates growth and maturation, especially of the brain and bones.

Cretinism occurs due to neonatal T3/T4 deficiencies and is marked by growth and maturation disorders (dwarfism, delayed sexual development, etc.) and central nervous disorders (intelligence deficits, seizures, etc.). The administration of thyroid hormones in the first six months of life can prevent or reduce some of these abnormalities.

Iodine metabolism (!D). Iodine circulates in the blood as either (1) inorganic I– (2–10 µg/L),

(2)organic non-hormonal iodine (traces) and

(3)protein-bound iodine (PBI) within T3 and T4 (35–80 µg iodine/L). The average daily requirement of iodine is ca. 150 µg; larger quantities are required in fever and hyperthyroidism (ca. 250–500 µg/day). Iodine excreted from the body must be replaced by the diet (!D). Sea salt, seafood, and cereals grown in iodine-rich soil are rich in iodine. Iodized salt is often used to supplement iodine deficiencies in the diet. Since iodine passes into the breast milk, nursing mothers have a higher daily requirement of iodine (ca. 200 µg/day).

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