BASIC SCIENCE

Physiology of the pituitary,thyroid and adrenal glandsRadu Mihai

AbstractThe pituitary gland is made of clusters of cells producing specific

hormones that control growth (growth hormones, GH), thyroid function

(TH), adrenal function (ACTH), gonadal function (FSH and LH). In addition,

the neurons that join the posterior pituitary (neurohypophysis) secrete

vasopressin – the antidiuretic hormone involved in maintaining water

balance.

The negative feedback loop is the basic mechanism to control the regu-

lation of all endocrine glands. Hypothalamic peptides – releasing

hormones (e.g. TRH, CRH) reach the hypophysis via the portal venous

system and induce the secretion of specific stimulating hormones (e.g.

TSH, ACTH) that drive the end-target endocrine cells to secrete hormones

(e.g. thyroid hormones - T3 and T4 or adrenal hormones – cortisol,

DHEAS). The plasma levels of these circulating hormones inhibit the pitu-

itary (short feedback) or the hypothalamus (long feedback) and limit the

further release of releasing- and stimulating- hormones.

The effects of circulating hormones on different tissues are mediated via

specific receptors on the cell membrane (e.g. vasopressin receptors), in

the cytoplasm (steroid receptor for cortisol) or in the nucleus (e.g. thyroid

hormone receptors). Understanding the physiological effects of peripheral

hormones helps understanding the mechanisms by which clinical signs

and symptoms developed in diseases characterised by excessive

hormone secretion (e.g. thyrotoxicosis, Cushing syndrome, phaeochromo-

cytomas) or lack of hormone secretion (e.g. diabetes insipidus).

Keywords Catecholamines; cortisol; hormone secretion regulation;

physiology; pituitary; thyroid hormones

Pituitary gland

The pituitary gland (hypophysis) lies beneath the hypothalamus,

in the sella turcica and is composed of two parts (Figure 1): the

anterior pituitary (adenohypophysis) is derived from ectoderm

and secretes protein hormones; the posterior pituitary (neuro-

hypophysis) is composed largely of hypothalamic neuronal axons

which form the pituitary stalk.

Secretion of hormones from the anterior pituitary is controlled

by hypothalamic hormones reaching the pituitary via a portal

system. The utility of this vascular system is that minute quan-

tities of hypothalamic hormones are carried directly to their

target cells in the anterior pituitary, and are not diluted out in the

systemic circulation.

Radu Mihai FRCS is a Consultant Endocrine Surgeon and Honorary

Senior Clinical Lecturer in the Department of Endocrine Surgery at John

Radcliffe Hospital, Oxford, UK. Conflicts of interest: none declared.

SURGERY 29:9 419

Growth hormone (GH)

GH is a 191 amino acid single-chain polypeptide synthesized in

somatotroph cells of the anterior pituitary. There are about ten

pulses of GH secretion/day. The predominant male ‘pulsatile’

secretion versus female ‘continuous’ secretion might explain the

different patterns of gene activation in target tissues, for example

induction of linear growth patterns and gain of body weight. GH

secretion is controlled as follows.

� GH-releasing hormone (GHRH) secreted by the hypothalamus

or as an ectopic secretion (e.g. from pancreatic cancers)

stimulates GH secretion.

� Somatostatin (SST) inhibits GH secretion. In addition SST has

multiple effects on pancreatic, liver and gastrointestinal

function it inhibits the secretion of CCK, glucagon, gastrin,

secretin, GIP, insulin and vasoactive intestinal peptide (VIP)

from the pancreas.

� Glucocorticoids have a biphasic effect on GH secretion: an

initial acute stimulation within 3 hours, followed by

suppression within 12 hours.

� Catecholamines: a-adrenergic pathways stimulate GH secre-

tion. The a2-agonist clonidine can therefore be used as

a provocative test of GH secretion. b-adrenergic pathways

inhibit secretion by increasing somatostatin release.

� Acetylcholine: muscarinic pathways stimulate GH secretion

by modulating somatostatinergic tone. Pyridostigmine, an

indirect agonist which blocks acetylcholinesterase, increases

the 24-hour secretion of GH. On the other hand, atropine

(muscarinic antagonist) blunts GH release.

� Endogenous opioids: endorphins and enkephalins stimulate

GH secretion in man and blockade with opiate antagonists

can attenuate the GH response to exercise.

� Exercise is a powerful stimulus to secretion of GH.

� Hypovolaemic shock, elective surgery, hypo- and hyper-

glycaemia, and malnutrition all cause increased GH release.

On the other hand, obesity is associated with lower GH levels,

partially due to decreased frequency of GH pulses.

� GH release is stimulated by a protein meal. L-arginine, an

essential amino acid, can be used as a provocative test for GH

secretion.

� Sleep: the amount of GH secreted during sleep is approxi-

mately triple the daytime rate. The decline in GH secretion

during ageing is parallelled by the decreasing proportion of

time spent in sleep. After sleep deprivation (e.g. experimental

or due to ‘jet lag’ when travelling across many time zones)

the magnitude of secretory spikes is augmented and the major

pulse of GH secretion occurs in late sleep.

Adrenocorticotrophic hormone (ACTH)

ACTH is released from corticotrophs. ACTH is derived from

a larger amino-acid precursor, pro-opiomelanocortin (POMC).

POMC transcription is positively regulated by corticotrophin-

releasing hormone (CRH) and negatively regulated by glucocor-

ticoids. Like GH, ACTH is secreted in pulses from corticotrophs

with about 40 pulses/24 hours, correlating with the pulsed

secretion of cortisol. ACTH levels vary in circadian rhythm, with

a peak at 0600e0900 hours and a trough at 2300e0200 hours.

Glucocorticoid feedback occurs at multiple levels: at the

pituitary (inhibition of POMC transcription), at the hypothalamus

(inhibition of CRH and AVP synthesis and release in the PVN),

� 2011 Elsevier Ltd. All rights reserved.

Pituitary gland: anatomical connections and functional role

Posterior

Pituitary lobe

Anterior

FSH, follicle-stimulating hormone.

Och

Hypothalamus

Dorsomedial nucleus

Paraventricular nucleus

Arcuate nucleus

Ventromedial nucleus

Preoptic

nucleiGonadotropin

FSH

Supraoptic

nucleus

Median eminenceGonadotropin FSH

Figure 1

BASIC SCIENCE

and most importantly, centrally at the level of the hippocampus,

which contains the highest concentration of glucocorticoid

receptors in the central nervous system.

ACTH release is increased by several factors, such as:

� CRH is a neuropeptide mainly found in the paraventricular

nuclei of the hypothalamus. Besides stimulating POMC tran-

scription and ACTH biogenesis, CRH stimulates the release of

ACTH, leading to a biphasic response with the fast release of

a pre-synthesized pool of ACTH, and the slower and sus-

tained release of newly synthesized ACTH.

� VIP stimulates ACTH secretion, a mechanism which may

explain the increase in ACTH after eating.

� Catecholamines stimulate CRH release via central a1-

adrenergic receptors.

� Interleukins (IL-1, IL-6 and possibly IL-2) e via short-term

effects on the hypothalamus.

� Stress induces the release of ACTH. The hypoglycaemia

during the insulin tolerance test is one such stressor.

Antidiuretic hormone (ADH)/vasopressin (AVP)

Arginine-vasopressin is a nine amino-acid peptide synthesized

within hypothalamic neurons and packaged in secretory vesi-

cles with a carrier protein called neurophysin, to be released

from the posterior pituitary. Vasopressin conserves body water

by reducing the loss of water in urine. It binds to receptors on

SURGERY 29:9 420

cells in the collecting ducts of the kidney and promotes the

insertion of ‘water channels’ (aquaporins) into the membranes

of kidney tubules, which transport solute-free water through

tubular cells and back into blood (water reabsorbtion), leading

to a decrease in plasma osmolarity and an increased osmolarity

of urine. High concentrations of ADH also cause widespread

constriction of arterioles, which leads to increased arterial

pressure.

ADH secretion is modulated by plasma osmolarity, which is

sensed in the hypothalamus by osmoreceptors. When plasma

osmolarity increases above a threshold, osmoreceptors stimulate

the neurons that secrete ADH. Hypothalamic osmoreceptors also

control the thirst sensation. The osmotic threshold for ADH

secretion is considerably lower than for thirst, hence thirst is

only activated if ADH alone cannot handle the increase in

osmolarity. Secretion of ADH is also simulated by decreases in

blood pressure and volume, conditions sensed by stretch recep-

tors in the heart and large arteries. For example, loss of 15e20%

of blood volume by haemorrhage results in massive secretion

of ADH.

Diabetes insipidus (DI) is due to a lack of ADH biological

activity:

� hypothalamic (‘central’) DI results from a deficiency in

secretion of ADH from the posterior pituitary (e.g. after head

trauma or infections or tumours involving the hypothalamus)

� 2011 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

� nephrogenic DI occurs when the kidneys are unable to

respond to ADH (e.g. renal disease or mutations in the ADH

receptor gene or gene encoding aquaporin-2).

The major sign of either type of diabetes insipidus is excessive

urine production. If AVP is completely absent, humans produce

as much as 16 litres of urine/day! Hypothalamic DI can be

treated with exogenous vasopressin (DDAVP).

Thyroid gland

The developing thyroid bud appears at the base of the tongue

( foramen caecum) and it migrates caudally from the pharyngeal

floor, passes through or in front of the hyoid bone and it reaches

its final position in front of the trachea. Along this migration

path, a connection between the foramen caecum and the thyroid

gland can persist as a thyroglossal duct.

Parafollicular C-cells derive from the neuroectoderm at the

level of the fourth pharyngeal pouch, merge with the developing

thyroid and end-up concentrated predominantly on the posterior

side of upper third of each thyroid lobe.

Thyroid follicles represent the dominant histological feature of

the mature thyroid gland (Figure 2). Thyroid cells surround

a central follicular lumen filled with a clear proteinaceous

colloid. The apical surface of the cells line the follicular lumen

and the basal part of each cell rests on a thin basement

membrane that isolates them from surrounding capillaries.

Calcitonin producing C-cells are identified easily in patients with

multiple endocrine neoplasia (MEN-2) presenting with C-cell

hyperplasia (Figure 2).

Iodine

Production of thyroid hormones is critically dependent on iodine,

deficiency of which can lead to endemic goitre, hypothyroidism

or cretinism (in children whose mothers had severe hypothy-

roidism) and favour the development of follicular thyroid cancer.

Conversely, excess iodine intake is associated with autoimmune

thyroid disease and papillary thyroid cancer.

Iodine is absorbed very efficiently in the gastrointestinal tract,

reaches the systemic circulation and is concentrated in the

follicular cells by a plasma membrane protein e the sodium-

iodine symporter (NIS). NIS activity allows for creating an

intracellular concentration of iodine some 40 times higher than

circulating levels, hence the thyroid contains >90% of total body

v

do

oc

m

ner g

p

bb

colloid

Histological appearance of the thyroid gland

Figure 2 Low and high power view of thyroid follicles. A thyroid follicular

cell, including: (a) apical vessel of cell; (e) endoplasmic reticulum; (d)

colloid droplets; (v) microvilli; (r) ribosomes on endoplasmic reticulum;

(g) Golgi apparatus; (m) mitochondrion; (p) plasma membrane; (c)

capillary cells; (n) nucleus; (b) basement membrane; (o) open ‘pore’

endothelial cells; (c) cilium.

SURGERY 29:9 421

iodine. Several other ions (pertechnetate, perchlorate) can be

transported by NIS. This forms the basis for the use of techne-

tium (99mTc) for thyroid scintigraphy.

The primary regulation of NIS is through thyroid-stimulating

hormone (TSH) and circulating iodine levels. Rapid increase in

iodine levels leads to a shut-down of iodine incorporation

(WolffeChaikoff effect), which is a protective mechanism

against iodine overload. This effect is beneficial in patients who

need rapid blockade of thyroid gland activity either for thera-

peutic reasons (e.g. patients with Graves’ disease who develop

allergic reaction to medication and need urgent thyroidectomy)

or prophylactic (e.g. after the fallout of radioactive iodine after

a nuclear accident such as the Chernobyl disaster in 1984).

Before administration of radioactive tracers marked with I131

or I123, the thyroid is ‘blocked’ by administration of potassium

iodide so that the intracellular stores are full and no further

uptake of radioactive iodine can take place.

High levels of TSH are critical for an efficient therapeutic

administration of radioactive iodine in patients with thyroid

cancers. This is achieved by redrawing the lyothyronine (T3)

replacement therapy some 10e14 days before the administration

of I131 (to induce TSH secretion from the pituitary) or by injecting

human recombinant TSH (Thyrogen).

Loss of NIS expression occurs in poorly differentiated thyroid

cancers hence such patients cannot benefit from radioactive

iodine treatment. There are ongoing efforts to identify drugs that

could induce NIS expression in such tumours with the hope of

re-establishing their ability to concentrate I131.

Within the follicular cells the iodine is oxidized to iodide and

transported into the follicular lumen by an iodineechloride

transporter e pendrin. Mutations in pendrin gene are associated

with congenital goitre and deafness.

Thyroglobulin (TG)

TG is a glycoprotein synthesized only by follicular cells and

represents the storage of thyroid hormones within the colloid.

Small amounts of colloid are engulfed through pinocytosis into

vesicles that are transported inside the follicular cells. Lysosomes

then fuse with these vesicles and release T4/T3. There is a fixed

ratio of each of these compounds formed, with each TG molecule

storing ten times more T4 than T3.

During the process of generating T4/T3, tyrosine residues on

the TG molecule are coupled with iodine. This iodination process

is called organification and is mediated by the enzyme thyroid

peroxidase (TPO). As a result, monoiodotyrosine (MIT) and di-

iodotyrosine (DIT) are formed. Subsequently TPO mediates the

coupling of MIT and DIT (forming active T3 or the inactive form e

reverse T3 hormone) or two DIT molecules to form T4. Anti-

thyroid drugs (carbimazole and propylthiouracil) inhibit the

enzymes involved in the synthesis of thyroid hormones.

Plasma TG levels are measured during follow-up after treatment

for thyroid cancer. In response to total thyroidectomy plus radio-

active iodine ablation it is expected that all thyroid tissue would be

destroyed hence TG would drop to undetectable levels and would

raise only in the presence of recurrent/metastatic disease.

Circulating thyroid hormones

In excess of 99% of circulating T4 and T3 are bound to plasma

proteins: thyroid-binding globulin (TBG, 75%), thyroid-binding

� 2011 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

prealbumin (TBPA, 15%), and albumin (10%). Only 0.02% of T4

and 0.4% of T3 are free in the circulation. As a greater percentage

of T4 is bound the half-life of T4 is longer (approximately 7 days)

compared with T3 (approximately 12e24 hours).

Because pregnancy and contraceptive pills can increase the

synthesis of binding proteins, such patients can have a higher

level of total T4/T3 but normal free T4(fT4)/free T3(fT3). This

effect also explains why pregnant women need an increased dose

of thyroxine substitution to maintain normal TSH levels.

Thyroid hormones can be displaced from its binding sites by

aspirin and non-steroidal anti-inflammatory drugs (NSAIDs).

Such drugs should be avoided in patients with severe thyrotox-

icosis as they can increase the level of free hormones hence

worsening the clinical signs.

Routine blood tests for thyroid functions tests (TFTs) include

measurement of TSH and fT4 levels. In primary hyperthyroidism

(e.g. Graves’ disease, toxic multinodular goitre) fT4 is raised and

TSH inhibited. In hypothyroidism (e.g. autoimmune thyroiditis,

post-thyroidectomy in the absence of T4 replacement) TSH is

raised in response low fT4/fT3.

Control of thyroid function by TSH

Thyroid-stimulating hormone (TSH) is a glycoprotein secreted by

pituitary cells through a feedback loop with T4/T3 levels

(Figure 3). The control cascade starts with TRH e produced in

the hypothalamus and released through the hypothalamic-

ColloidH2O

2Iodide

Tg (MIT, DIT, T3 and T

4)

T3 and T

4Iodide

Tg

E

TPODUOX

TSH-R

Pendrin, AIT

Nucleus

mRNA

mRNA

Transcription

NIS C

A

B

D

Protein synthesis

NIS gene

Regulation of thyroid function and intracellular effects of thyroid hormones

Figure 3 TSH signalling via the TSH receptor (which is shown at the

bottom of the thyrocyte on the left) controls thyroid hormone synthesis,

and it can increase expression of NIS in the basolateral membrane of

thyrocytes. The proteins involved in efflux of iodide at the apical

membrane are not known, and the roles of AIT and pendrin are unclear. As

shown in the left-hand thyrocyte, iodide is organified in the tyrosyl resi-

dues of Tg in a reaction catalysed by TPO, in the presence of H2O2, which

is produced by DUOX. Tg contains MIT, DIT, T3, and T4 and is stored in

colloid until T3 and T4 need to be released into the blood. AIT, apical

iodine transporter; DIT, di-iodotyrosine; DUOX, dual oxidase; MIT,

monoiodotyrosine; NIS, sodium-iodide symporter; Tg, thyroglobulin;

TPO, thyroid peroxidase; TSH-R, TSH receptor; mRNA, messenger RNA.

SURGERY 29:9 422

pituitary circulation onto the pituitary. TRH then stimulates the

thyrotroph cells to produce TSH.

TSH acts on specific receptors on the membrane of follicular

cells and stimulates the activity of NIS (i.e. stimulates iodine

uptake) and of intracellular enzymes involved in thyroid

hormone synthesis (i.e. stimulates synthesis of TG iodination of

tyrosine resides on TG).

Mutations in TSH receptor structure lead to autonomous stim-

ulation (toxic adenoma, Plummer’s adenoma). On I123 scan the

overactive nodule appears ‘hot’ as it is able to incorporate iodine

without the need of circulating TSH while the rest of the gland

appears ‘cold’ (i.e. does not incorporate I* asNIS activity in normal

follicular cells is absent if TSH is suppressed) (Figure 4).

Activating autoantibodies against the TSH receptors are

present in Graves’ disease.

Conversion of T4 into T3

The enzyme 50-deiodinase converts T4 into the metabolically

active T3 in liver/muscle (type I deiodinase) and brain (type II

deiodinase). Type III deiodinase inactivates thyroid hormones.

The balance between the activity of each of these enzymes in

disturbed in stress. All these enzymes require selenium for their

activity hence lack of selenium leads to abnormal thyroid function.

Cellular effects of thyroid hormones

Plasma membranes of various cells have unique hormone recep-

tors/transporters for uptake of thyroid hormones. Within the cells

T3 translocates into the nucleus, binds to nuclear receptors (TR,

see Figure 3) then couples to thyroid responsive elements (TRE, see

Figure 3) on the promoters of target-genes. This process can

enhance or inhibit the expression of target-genes.

Thyroid hormones play an important role in development:

they are critical for normal development of the skeletal system

and musculature and are essential for normal brain development

and regulates synaptogenesis, neuronal integration, myelination

and cell migration.

Metabolic effects of thyroid hormones include regulation of

basal metabolic rate and increasing oxygen consumption in most

target tissues. In addition, thyroid hormones increase the sensi-

tivity of target tissues to catecholamines, thereby elevating

lipolysis, glycogenolysis, and gluconeogenesis.

Physiology of thyroid crisis: a sudden rise in the level of thyroid

hormones leads to thyrotoxic crisis. Seldom seen, it can be trig-

gered by operating on thyrotoxic patients poorly controlled by

Thyroid uptake scan

Figure 4 Intense uptake of technetium into a ‘hot’ nodule. Note that the

rest of the thyroid is not apparent as no uptake can occur in the normal

thyroid tissue in the absence of thyroid-stimulating hormone.

� 2011 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

medication. Signs include severe tachycardia, pyrexia and

neurological signs including coma. Treatment involves blocking

thyroid secretion (by high-dose oral iodine, see above) and

inhibiting the synthesis of thyroid hormones (by using carbi-

mazole or propylthiouracil), decreasing the peripheral conver-

sion of T4 into T3 (propranolol, steroids) and by avoiding

displacement of thyroid hormones from binding proteins (i.e.

avoid the use of aspirin or NSAIDs).

Calcitonin

Calcitonin belongs to a larger family called calcitonin gene-related

peptides(CGRP)thataresecretedinthebrainandgastrointestinaltract.

High calcium levels stimulate calcitonin release and this leads

to homeostatic inhibition of osteoclast activity (i.e. less bone

resorption). This physiological mechanism explains the rationale

for using calcitonin in the treatment of osteoporosis and Paget’s

disease (though the clinical efficacy is minimal).

The role of calcitonin in human biology remains vague. There

are no known side effects of low calcitonin levels and very high

levels (e.g. in patients with medullary thyroid carcinoma) have

no impact on calcium homeostasis.

Adrenal glands

The adrenal glands are located on the medial side of the upper

pole of each kidney and are formed by two areas e the cortex and

the medulla, with different embryological origins and different

physiological functions. The adrenal cortex represents around

85% of the adrenal gland weight and surrounds the adrenal

medulla (Figure 5).

The steroid hormones of the adrenal cortex are derivatives of

cholesterol. Based on the total number of carbon atoms, the prin-

cipal types of hormones are either C21 (e.g. cortisol, aldosterone)

or C19 (androgens).

Glucocorticoids

The hypothalamic-pituitary axis (HPA) regulates the adrenal

release of glucocorticoids. Hypothalamic release of corticotropin-

releasing hormone (CRH) stimulates the pituitary gland to

produce ACTH, which in turn acts on the adrenal cortex to stim-

ulate the release and synthesis of cortisol. Cortisol then completes

the cycle by exerting negative feedback on CRH and ACTH release.

This feedback mechanism is lost in patients with Cushing’s

syndrome (i.e. with an autonomous unilateral adrenal adenoma

producing excess cortisol) in whom large doses of dexamethasone

fail to suppress the endogenous production of cortisol. In contrast,

patients with Cushing’s disease (pituitary adenoma producing

ACTH) respond to the inhibition by high dose dexamethasone (8

mg/day for 2 days) by decreasing the urinary excretion of cortisol.

HPA axis testing: to assess whether the HPA axis is functional

(e.g. after long-term steroid therapy) cortisol secretion is stimu-

lated with synthetic ACTH (cosyntropin 250 mg) and serum

cortisol levels are measured 30e60 minutes later. Normal

response is defined as a serum cortisol of at least 600.

Glucocorticoid levels have a diurnal variation with a morning

peak (0400e0800 hours) and minimal nocturnal through

(0200e0400 hours). Synthesis of cortisol can increase five- to

tenfold under conditions of severe stress. A loss of this circadian

rhythmicity is seen in patients with Cushing’s syndrome.

SURGERY 29:9 423

Action of glucocorticoids (Figure 6): glucocorticoids diffuse

passively across the cellular membrane and bind to the intracel-

lular glucocorticoid receptor (GR) expressed in almost every cell in

the body. GR regulates genes controlling the development,

metabolism and immune response. Because the GR gene is

expressed in several forms, it hasmany different effects in different

parts of the body.

In the absence of cortisol, the glucocorticoid receptor (GR)

resides in the cytosol complexed with a variety of proteins

including heat shock proteins (hsp90, hsp70). After the receptor

binds to glucocorticoid, the receptoreglucocorticoid complex has

two principal mechanisms of action:

� Transactivation: a direct mechanism of action involving

homodimerization of the receptor, translocation via active

transport into the nucleus, and binding to specific DNA

sequences ( glucocorticoid responsive elements, or GREs). This

results in either enhancement or suppression of transcription

of susceptible downstream genes with the biological response

dependent on the cell type

� Transrepression: activated GR binds with other transcription

factors and prevents them from binding to their target-genes

and hence represses the expression of genes that are nor-

mally upregulated by nuclear factor kappa B (NF-kB) or

activator protein-1 (AP-1) (e.g. pro-inflammatory mediators).

Anti-inflammatory effects: glucocorticoids have inhibitory

effects on a broad range of specific immune responses mediated

by T cells and B cells, as well as potent suppressive effects on

the functions of phagocytes. Through their inhibitory effects on

both acquired and innate immunologic function, glucocorticoids

are remarkably efficacious in managing many of the acute

disease manifestations of inflammatory and autoimmune

disorders.

Side effects of glucocorticoids are mostly seen with oral and

injectable glucocorticoids, but can be seen with inhaled and

topical steroids at higher doses. Glucocorticoid toxicity is related

to both the average dose and cumulative duration of use:

� Osteoporosis: is one of the most debilitating complications of

glucocorticoid therapy. Several mechanisms are involved:

decline in bone formation (through a direct inhibition of oste-

oblasts and osteoblasts’ apoptosis), increase in bone resorp-

tion, a decrease in gastrointestinal absorption of calcium,

increase in urinary calcium excretion, and a decrease in

gonadal steroids production. Bone loss can be rapid and

substantial: as much as 25e30% of bone loss can occur in the

spine during the first year of therapy. A substantial increase in

fracture risk can occurwithin 3e6months of steroid treatment.

If steroids are discontinued, bone improves substantially after

6e24 months

� Hyperglycaemia: glucocorticoids increase hepatic glucose

production (in part by increasing substrate availability

through proteolysis and lipolysis), induce insulin resistance

and hyperinsulinaemia and inhibit glucose transport into cells

� Hypertension: glucocorticoids raise blood pressure in both

normotensive and hypertensive patients. The pathogenesis is

multi-factorial, involving increased peripheral vascular

sensitivity to adrenergic agonists, increased hepatic produc-

tion of angiotensinogen (renin substrate), and activation of

renal mineralocorticoid receptors.

� 2011 Elsevier Ltd. All rights reserved.

Cholesterol

Steroid hormone synthesis pathways

Pregnenolone

Progesterone DHEA

Ovaries

EstroneEstradiol

EstriolProgesterone

Androstenedione

TestosteroneAndrostenedione

Testes

Aldosterone

Kidneys

AndrostenedioneCortisol

Liver

Aldosterone Cortisone

Adrenal glands

Normal pathway Adrenal fatigue / Pregnenolone steal

Factors actingon the gland

Zona fasciculata

Zona reticularis

Zona glomerulosa

Angiotensin andcorticotropin

(ACTH)

Capillaries

Corticotropin

Corticotropin

Androgens

Glucocorticoids

Androgens(dihydroepiandrosteroneandrostenedione)

Mineralocorticoids(aldosterone)

Glucocorticoids(cortisol andcorticosterone)

Hormonesecreted

Structure of the adrenal cortex morphological structure (a) and biochemical pathways for steroid hormones synthesis (b)

a

b

ACTH, adrenocorticotrophic hormone; DHEA, dehydroepiandrosterone.

Figure 5

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SURGERY 29:9 424 � 2011 Elsevier Ltd. All rights reserved.

Mechanisms of action of cortisol

Cortisol

Cytoplasmic

activation

Active GR

monomer

Dimerization

Transcription

GRE

GR, glucocorticoid receptor; GRE, glucocorticoid responsive element; hsp, heat shock protein.

GRhsp90

hsp90

hsp90

hsp90

hsp90FKBP52

FKBP52

FKBP52hsp90

hsp70

hsp70

hsp70

GR

GR

GR

GR

GRGR

Figure 6

BASIC SCIENCE

The mineralocorticoids

Aldosterone is synthesized and released from zona glomerulosa

of the adrenal cortex. Aldosterone secretion is regulated by the

renin-angiotensin system and is independent of ACTH therefore

patients with secondary adrenal insufficiency due to previous

glucocorticoid therapy have intact aldosterone secretion.

In response to a decrease in intravascular volume, renin is

released from the juxtaglomerular cells located in the wall of the

afferent glomerular arterioles. Renin cleaves angiotensinogen

into angiotensin I, which is further converted into angiotensin II

by the angiotensin-converting enzyme (ACE). Angiotensin II has

two effects: it acts as a potent vasoconstrictor and stimulates the

release of aldosterone by binding to plasma membrane receptors

on adrenal cells in the zona glomerulosa.

In addition to the renin-angiotensin system, high Kþ increases

aldosterone levels and severe Naþ depletion stimulates the

conversion of corticosterone into aldosterone.

Aldosterone binds to minerolocorticoid receptors in the distal

tubules and cortical collecting tubes of the kidney. It increases

sodium absorption through the Naþ-channels. This leads to

expanded intravascular volume and suppresses renin secretion.

Part of the urinary Naþ is exchanged with Kþ and Hþ.In primary hyperaldosteronism (Conns’ syndrome), excess

aldosterone leads to high blood pressure, suppressed renin levels,

SURGERY 29:9 425

increased urinary extraction of Kþ (leading to hypokalaemia) and

Hþ (i.e. acidic urine).

Rationale for Conn’s diagnosis: primary hyperaldosteronism is

a common cause of hypertension. Excess secretion of aldosterone

from a small adrenal adenoma or from bilateral hyperplasia leads

to hypokalaemia and hypertension. Screening for this condition

in a hypertensive patient relies on measuring the aldosterone/

renin ratio (high in primary hyperaldosteronism, low in other

forms of hypertension).

Adrenal androgens

At the onset of puberty, the adrenal starts to secrete weak

androgens that trigger the appearance of pubic and axillary hair.

During adulthood adrenal androgens have minimal contribution

(testicles produce much larger quantities). During menopause

the adrenal is an important source of oestrogens. Of historical

interest only, adrenalectomy was once performed as part of the

treatment for advanced breast cancer.

Basics of congenital adrenal hyperplasia (CAH): CAH is

a genetic condition leading to a deficit of one of the enzymes

involved in cortisol synthesis. The persistently low cortisol

stimulates ACH secretion and this drives the adrenal hyperplasia.

� 2011 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

The precursors of cortisol accumulate upstream of the deficient

enzyme and are diverted towards production of androgens.

Themost common is the deficit of 21-hydroxylase. In the female

fetus it leads to variable degrees of virilization of external genitalia,

possibly with complete closure of labia (that can be confused with

a scrotum) and enlargement of clitoris (pseudohermaphroditism).

The young girl born with ambiguous genitalia may therefore be

declared a boy and the diagnosis be delayed for many years. In

a minority of cases the enzymatic block is extremely severe and

impairs the production of aldosterone leading to severe salt-losing

state. Treatment of this condition consists of steroid replacement.

Adrenal medulla

Adrenal medulla derives from the neuroectoderm. In the second

month of gestation cells from the neural crest (sympatogonia)

migrate to form the sympathetic system (neuroblasts) or the

adrenal medulla primordium (phaeochromoblasts). Similar cells

are present in extra-adrenal tissues, predominantly around the

aorta (e.g. organof Zuckerkandl, at the bifurcation of the aorta) but

also in the neck and rarely in the bladder. Such cells can give rise to

extra-adrenal phaeochromocytomas, called paragangliomas.

One characteristic in common with neurons is the expression

of the norepinephrine uptake mechanism. This uptake mecha-

nism is responsible for incorporation of MIBG (meta-iodine-

Adrenergic receptors and their physiological effects

Tissue

a1 Smooth muscle

- Blood vessels

- Bronchi

- Bladder

- Iris (radial muscle)

- Cardiac

Liver

a2 Blood vessels

Pancreatic b-cells

Sympathetic nerve endings

b1 Heart

Juxtaglomerular cells

Sympathetic nerve endings

b2 Smooth muscle

- Blood vessels

- Bronchi

- Bladder

Heart

Sympathetic nerve endings

Pancreatic b-cells

Skeletal muscle

b3 Fat

Subcutaneous tissue

ADR, adrenaline; NA, noradrenaline.

Table 1

SURGERY 29:9 426

benzylguanetidine) into chromaffin cells. This compound can be

marked with radioactive iodine and used as a radiopharmaceu-

tical for imaging phaeochromocytomas (when labelled with I123,

which has a short half-life) or for treating malignant phaeo-

chromocytomas (when labelled with I131, which has a longer

half-life).

Synthesis of catecholamines

In the cytoplasm tyrosine hydroxylase converts tyrosine into

dihydroxyphenylalanine (DOPA) and DOPA-decarboxylase gener-

ates dopamine. Dopamine is actively incorporated into secretory

granules and is then converted into norepinephrine. Some chro-

maffin cells convert norepinephrine into epinephrine if they express

the enzyme PNMT (phenyl-ethanolamine-N-methyltransferase).

PNMT expression is induced by cortisol, whose high concentration

into adrenal vein drives the production of epinephrine from normal

adrenal.

Lack of cortisol-induced PNMT expression explains why extra-

adrenal phaeochromocytomas (i.e. paragangliomas) produce

predominantly/exclusively norepinephrine.

Secretory granules also contain chromogranin, neuropeptide

Y, enkephalins, somatostatin, though their physiological signifi-

cance is unclear. Plasma levels of chromogranins are monitored

in patients with neuroendocrine tumours as a diagnostic test and

a marker of response after therapy.

Action Sensitivity

NA ¼ ADR

Vasoconstriction

Bronchoconstriction

Contraction

Contraction (mydriasis)

Contraction

Glycogenolysis

Vasoconstriction ADR > NA

Decreased insulin secretion

Decreased NA release

Increased contraction NA ¼ ADR

Tachycardia

Increased renin secretion

Increased NA release

ADR >> NA

Vasodilatation

Bronchodilatation

Relaxation

Increased rte/contraction

Increased NA release

Increased insulin secretion

Tremor

Thermogenesis NA >> ADR

Lipolysis

� 2011 Elsevier Ltd. All rights reserved.

BASIC SCIENCE

Degradation of catecholamines

COMT (catechol O-methyltransferase) generates metanephrines

by converting noradrenaline into normetadrenaline and adrena-

line into metadrenaline. This is a constant process that takes

place both into normal and tumour cells. Measurement of met-

anephrines in a 24-hour urine specimen is the most accurate test

for diagnosing a phaeochromocytoma.

The end product of catecholamine metabolism is VMA

(vanilylmandelic acid) whose urine concentration is now an

SURGERY 29:9 427

outdated test for diagnosis of phaeochromocytomas. Only a very

small amount of catecholamines are secreted in the urine as free

dopamine/free-adrenaline/free-noradrenaline.

Biological activity of catecholamines

Dopamine in the systemic circulation acts on dopaminergic

receptors in the splanchnic vessels to induce vasodilatation. The

effects of noradrenaline and adrenaline are mediated by two

types of receptors e a and b (Table 1). A

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