Pituitary and adrenal hormones and the drugs that act on them

(Glucocorticoids)

The pituitary and adrenal glands are major sites for the synthesis and release of hormones that profoundly affect the biochemistry and physiology of almost all cells, and which are crucial to the understanding of the actions of many endocrine, anti-inflammatory and other drugs

The anterior pituitary The anterior pituitary glandgland

The anterior pituitary gland secretes The anterior pituitary gland secretes hormones that regulate: hormones that regulate: the release of the release of glucocorticoidsglucocorticoids from from

adrenal cortex ACTHadrenal cortex ACTH the release of the release of thyroid hormonesthyroid hormones TSH TSH ovulationovulation in the female and in the female and

spermatogenesis in the male, and the spermatogenesis in the male, and the release of sex hormonesrelease of sex hormones LH&FSH LH&FSH

growthGHgrowthGH mammary glandmammary gland structure and structure and

function PRL function PRL

Each anterior pituitary hormone is regulated by Each anterior pituitary hormone is regulated by a specific hypothalamic releasing factor. a specific hypothalamic releasing factor. Feedback mechanisms govern the release of Feedback mechanisms govern the release of these factors. Substances available for clinical these factors. Substances available for clinical use include: use include: growth hormone-releasing factorgrowth hormone-releasing factor (sermorelin) (sermorelin)

and analogues of growth hormone and analogues of growth hormone (somatrem , somatropin) (somatrem , somatropin)

thyrotrophin-releasing factorthyrotrophin-releasing factor (protirelin ) and (protirelin ) and thyroid-stimulating hormonethyroid-stimulating hormone (thyrotrophin; (thyrotrophin; used to test thyroid function) used to test thyroid function)

octreotide and lanreotide, octreotide and lanreotide, analogues of analogues of somatostatin,somatostatin, which inhibit growth hormone which inhibit growth hormone release release

corticotrophin-releasing factor, used in corticotrophin-releasing factor, used in diagnosis diagnosis

gonadotrophin-releasing factor. gonadotrophin-releasing factor.

Posterior pituitaryPosterior pituitary

The posterior pituitary secretes: The posterior pituitary secretes: oxytocinoxytocin antidiuretic hormone (vasopressin ), antidiuretic hormone (vasopressin ),

which acts on V2 receptors in the which acts on V2 receptors in the distal kidney tubule to increase water distal kidney tubule to increase water reabsorption and, in higher reabsorption and, in higher concentrations, on V1 receptors to concentrations, on V1 receptors to cause vasoconstriction. It also cause vasoconstriction. It also stimulates adrenocorticotrophic stimulates adrenocorticotrophic hormone secretion. hormone secretion.

Substances available for clinical use are Substances available for clinical use are vasopressin and the analogues vasopressin and the analogues desmopressin and terlipressin.desmopressin and terlipressin.

Clinical use of antidiuretic Clinical use of antidiuretic hormone (vasopressin ) and hormone (vasopressin ) and

analogues.analogues. Diabetes insipidus: lypressin, desmopressin. Diabetes insipidus: lypressin, desmopressin. Initial treatment of bleeding oesophageal Initial treatment of bleeding oesophageal

varices: vasopressin , terlipressin, lypressin. varices: vasopressin , terlipressin, lypressin. (Octreotide-a somatostatin analogue-is also (Octreotide-a somatostatin analogue-is also used, but direct injection of sclerosant via used, but direct injection of sclerosant via an endoscope is the main treatment.) an endoscope is the main treatment.)

Prophylaxis against bleeding in haemophilia Prophylaxis against bleeding in haemophilia (e.g. before tooth extraction): vasopressin , (e.g. before tooth extraction): vasopressin , desmopressin (by increasing the desmopressin (by increasing the concentration of factor VIII). concentration of factor VIII).

Felypressin is used as a vasoconstrictor Felypressin is used as a vasoconstrictor with local anaesthetics.with local anaesthetics.

Desmopressin is used for persistent Desmopressin is used for persistent nocturnal enuresis in older children and nocturnal enuresis in older children and adults. adults.

Adrenal Anatomy

• small, triangular glands loosely attached to the kidneys

• divided into two morphologically and distinct regions

- adrenal cortex (outer)

- adrenal medulla (inner)

Adrenocorticotrophic Adrenocorticotrophic hormone (corticotrophin) & hormone (corticotrophin) &

adrenal steroidsadrenal steroids Adrenocorticotrophic hormone (ACTH) Adrenocorticotrophic hormone (ACTH)

stimulates synthesis and release of stimulates synthesis and release of glucocorticoids (e.g. hydrocortisone ), and glucocorticoids (e.g. hydrocortisone ), and also some androgens, from the adrenal also some androgens, from the adrenal cortex. cortex.

Corticotrophin-releasing factor from the Corticotrophin-releasing factor from the hypothalamus regulates ACTH release, and hypothalamus regulates ACTH release, and is regulated in turn by neural factors and is regulated in turn by neural factors and negative feedback effects of plasma negative feedback effects of plasma glucocorticoids. glucocorticoids.

Mineralocorticoid (e.g. aldosterone) release Mineralocorticoid (e.g. aldosterone) release from the adrenal cortex is controlled by the from the adrenal cortex is controlled by the renin-angiotensin system. renin-angiotensin system.

Adrenal Cortex

•Hormones produced by the adrenal cortex are referred to as corticosteroids.

•These comprise mineralocorticoids, glucocorticoids and sex steriods.

•The cortex is divided into three regions:

•zona glomerulosa• zona fasciculata• zona reticularis

Regulation of Cortisol Release cont

Enhanced release can be caused by:

• physical trauma

• infection

• extreme heat and cold

• exercise to the point of exhaustion

• extreme mental anxiety

GlucocorticoidsGlucocorticoids Common drugs used include hydrocortisone , Common drugs used include hydrocortisone ,

prednisolone and dexamethasone .prednisolone and dexamethasone . Metabolic actionsMetabolic actions CarbohydratesCarbohydrates: decreased uptake and utilization of : decreased uptake and utilization of

glucose accompanied by increased gluconeogenesis; glucose accompanied by increased gluconeogenesis; this causes a tendency to hyperglycaemia. this causes a tendency to hyperglycaemia.

ProteinsProteins: increased catabolism, reduced anabolism. : increased catabolism, reduced anabolism. LipidsLipids: a permissive effect on lipolytic hormones and a : a permissive effect on lipolytic hormones and a

redistribution of fat, as observed in Cushing's syndrome. redistribution of fat, as observed in Cushing's syndrome. NoneRegulatory actionsNoneRegulatory actions Hypothalamus and anterior pituitary glandHypothalamus and anterior pituitary gland: a negative : a negative

feedback action resulting in reduced release of feedback action resulting in reduced release of endogenous glucocorticoids. endogenous glucocorticoids.

Cardiovascular systemCardiovascular system: reduced vasodilatation, : reduced vasodilatation, decreased fluid exudation. decreased fluid exudation.

MusculoskeletalMusculoskeletal: decreasing osteoblast and increasing : decreasing osteoblast and increasing osteoclast activityosteoclast activity. .

Inflammation and immunityInflammation and immunity: : acute inflammationacute inflammation: decreased influx and activity of : decreased influx and activity of

leucocytes leucocytes chronic inflammationchronic inflammation: decreased activity of : decreased activity of

mononuclear cells, decreased angiogenesis, less fibrosis mononuclear cells, decreased angiogenesis, less fibrosis lymphoid tissueslymphoid tissues: decreased clonal expansion of T and B : decreased clonal expansion of T and B

cells, and decreased action of cytokine-secreting T cells. cells, and decreased action of cytokine-secreting T cells. MediatorsMediators: : decreased production and action of cytokines, decreased production and action of cytokines,

including interleukins, tumour necrosis factor-α including interleukins, tumour necrosis factor-α and granulocyte macrophage colony-stimulating and granulocyte macrophage colony-stimulating factor factor

reduced generation of eicosanoids reduced generation of eicosanoids decreased generation of IgG decreased generation of IgG decrease in complement components in the decrease in complement components in the

blood blood increased release of anti-inflammatory factors increased release of anti-inflammatory factors

such as interleukin-10 and annexin 1. such as interleukin-10 and annexin 1. Overall effectsOverall effects: reduction in the activity of the : reduction in the activity of the

innate and acquired immune systems, but also innate and acquired immune systems, but also decreased healing and diminution in the decreased healing and diminution in the protective aspects of the inflammatory response. protective aspects of the inflammatory response.

The principal adrenal steroids are those with mineralocorticoid and glucocorticoid activity, but some sex steroids-mainly androgens-are also secreted. The mineralocorticoids affect water and electrolyte balance and the main endogenous hormone is aldosterone. The glucocorticoids affect carbohydrate and protein metabolism and the main endogenous hormones are hydrocortisone and corticosterone. The two actions are not completely separated in naturally occurring steroids, some glucocorticoids having quite substantial effects on water and electrolyte balance

.* In addition to their metabolic effects, glucocorticoids also have anti-inflammatory and immuno-suppressive activity, and it is for these actions that they are most commonly used therapeutically. When they are used as anti-inflammatory and immunosuppressive agents, all of their other actions are unwanted side-effects

Natural and Synthetic Natural and Synthetic AdrenocorticosteroidsAdrenocorticosteroids

Antiinflamm Salt retainingAntiinflamm Salt retaining

GlucocorticoidsGlucocorticoids

Short actingShort acting hydrocortisone, cortisonehydrocortisone, cortisone ++ + + prednisone, prednisolone,prednisone, prednisolone, methylprednisolonemethylprednisolone ++++ ++ ++ Intermediate actingIntermediate acting triamcinolonetriamcinolone ++++ fluprednisolonefluprednisolone ++++ ++++ Long actingLong acting dexamethasonedexamethasone ++++ ++++

MineralocorticoidsMineralocorticoids deoxycorticosteronedeoxycorticosterone ++ ++++ ++++

Synthetic steroids have been developed in which it has been possible to separate the glucocorticoid from the mineralocorticoid actions, but it has not been possible to separate the anti-inflammatory actions from the other actions of the glucocorticoids.

Hormones of the Adrenal Cortex

• all adrenal cortex hormones are steroid

• not stored, synthesized as needed

O

HO

O

C = O

HOOH

CH2OH

testosterone cortisol

Mechanism of action of the glucocorticoids

Glucocorticoids interact with intracellular receptors; the resulting steroid-receptor complexes dimerise (form pairs) then interact with DNA to modify gene transcription: inducing synthesis of some proteins and inhibiting synthesis of others.

For metabolic actions, most mediator proteins are enzymes, e.g. cAMP-dependent kinase, but not all actions on genes are known.

For anti-inflammatory and immunosuppressive actions, some actions at the level of the genes

are known:

inhibition of transcription of the genes for cyclooxygenase-2, cytokines (e.g. the interleukins), cell adhesion molecules and the inducible form of nitric oxide synthase

block of vitamin D3-mediated induction of the osteocalcin gene in osteoblasts and modification of transcription of the collagenase genes

increased synthesis of annexin-1, which is important in negative feedback on the hypothalamus and anterior pituitary and may have anti-inflammatory actions.

Some non-genomic (rapid) effects of glucocorticoids have also been observed.

GlucocorticoidsGlucocorticoids

Drugs used: hydrocortisone , prednisolone and Drugs used: hydrocortisone , prednisolone and dexamethasone . dexamethasone .

Metabolic actionsMetabolic actions On carbohydrates: decreased uptake and On carbohydrates: decreased uptake and

utilisation of glucose and increased utilisation of glucose and increased gluconeogenesis; this causes a tendency to gluconeogenesis; this causes a tendency to hyperglycaemia. hyperglycaemia.

On proteins: increased catabolism, reduced On proteins: increased catabolism, reduced anabolism. anabolism.

On fat: a permissive effect on lipolytic hormones, On fat: a permissive effect on lipolytic hormones, and a redistribution of fat, as in Cushing's and a redistribution of fat, as in Cushing's syndrome.syndrome.

Cushing’s Syndrome

Regulatory actions

On hypothalamus and anterior pituitary: a negative feedback action resulting in reduced release of endogenous glucocorticoids.

On vascular events: reduced vasodilatation, decreased fluid exudation. On cellular events:

in areas of acute inflammation: decreased influx and activity of leucocytes

in areas of chronic inflammation: decreased activity of mononuclear cells, decreased proliferation of blood vessels, less fibrosis

in lymphoid areas: decreased clonal expansion of T and B cells and decreased action of cytokine-secreting T cells.

On inflammatory and immune mediators: decreased production and action of cytokines including

many interleukins, tumour necrosis factor-γ, granulocyte-macrophage colony-stimulating factor

reduced generation of eicosanoids decreased generation of IgG decrease in complement components in the blood.

Overall effects: reduction in chronic inflammation and autoimmune reactions but also decreased healing and diminution in the protective aspects of the inflammatory response.

Untoward Effects of GlucocorticoidsUntoward Effects of Glucocorticoids

Due to:Due to: Prolonged useProlonged use: fever, myalgia, malaise, : fever, myalgia, malaise,

fluid and electrolyte imbalance, fluid and electrolyte imbalance, hypertension, hyperglycemia, myopathy, hypertension, hyperglycemia, myopathy, increased infections, ulcers, behavioral increased infections, ulcers, behavioral changes; pituitary-adrenal suppressionchanges; pituitary-adrenal suppression

Abrupt withdrawalAbrupt withdrawal after prolonged useafter prolonged use: : acute adrenal insufficiencyacute adrenal insufficiency

unwanted actions of the glucocorticoids

Administration can be oral, topical and parenteral. Administration can be oral, topical and parenteral. The drugs are bound to corticosteroid-binding The drugs are bound to corticosteroid-binding globulin in the blood and enter cells by diffusion. globulin in the blood and enter cells by diffusion. They are metabolised in the liver. They are metabolised in the liver.

Unwanted effects are seen mainly with prolonged Unwanted effects are seen mainly with prolonged systemic use as anti-inflammatory or systemic use as anti-inflammatory or immunosuppressive agents (in which case all the immunosuppressive agents (in which case all the metabolic actions are unwanted), but not usually metabolic actions are unwanted), but not usually with replacement therapy. The most important are: with replacement therapy. The most important are: suppression of response to infection suppression of response to infection suppression of endogenous glucocorticoid synthesis suppression of endogenous glucocorticoid synthesis metabolic actions (see above) metabolic actions (see above) osteoporosis osteoporosis iatrogenic Cushing's syndromeiatrogenic Cushing's syndrome

Untoward Effects of GlucocorticoidsUntoward Effects of Glucocorticoids

Cardiovascular SystemCardiovascular System Prolonged Use: hypertension due to increased Na+ uptake Prolonged Use: hypertension due to increased Na+ uptake Rapid withdrawal: toxicity secondary to decreased Na+ uptake Rapid withdrawal: toxicity secondary to decreased Na+ uptake

(hypocortism) (hypocortism) Direct effects due to steroid receptors on heart and smooth Direct effects due to steroid receptors on heart and smooth

muscle; increased cardiac output and vascular tone muscle; increased cardiac output and vascular tone

Skeletal MuscleSkeletal Muscle Impaired functioningImpaired functioning Muscle weakness and wastingMuscle weakness and wasting

Untoward Effects of GlucocorticoidsUntoward Effects of Glucocorticoids Central Nervous SystemCentral Nervous System

Increased mood; euphoriaIncreased mood; euphoria Behavioral changes; psychosisBehavioral changes; psychosis EEG abnormalitiesEEG abnormalities Increased excitability of nervous tissueIncreased excitability of nervous tissue

Gastrointestinal SystemGastrointestinal System Increased gastric acid secretionIncreased gastric acid secretion Increased fat absorptionIncreased fat absorption

Endocrine SystemEndocrine System ACTH↓, ↓ TSH , ↓ FSHACTH↓, ↓ TSH , ↓ FSH

1

Clinical Therapeutics 11

GC are widely used for the GC are widely used for the suppression of inflammation in suppression of inflammation in chronic inflammatory diseases such chronic inflammatory diseases such as asthma, RA, inflammatory bowel as asthma, RA, inflammatory bowel disease and autoimmune diseases, disease and autoimmune diseases, all with increased expression of all with increased expression of inflammatory genes.inflammatory genes.

Clinical Therapeutics

Adrenal Cortical InsufficiencyAdrenal Cortical Insufficiency

AcuteAcute:: life threatening; associated with abrupt withdrawal after life threatening; associated with abrupt withdrawal after prolonged therapy; GI abnormalities; dehydration, decreased Na+, prolonged therapy; GI abnormalities; dehydration, decreased Na+, increased K+ leads to CV weakness, lethargy, hypotensionincreased K+ leads to CV weakness, lethargy, hypotension Treatment: water, salt, cortisol, glucoseTreatment: water, salt, cortisol, glucose

Chronic:Chronic: (Addison’s disease): weakness, fatigue, decreased (Addison’s disease): weakness, fatigue, decreased blood glucose, minor infections can lead to septic shockblood glucose, minor infections can lead to septic shock Treatment: Treatment: cortisolcortisol

Therapeutics

Adrenal HyperplasiaAdrenal Hyperplasia Congenital adrenal hyperplasiaCongenital adrenal hyperplasia

defect in cortisol synthesis; compensatory defect in cortisol synthesis; compensatory increase in ACTH increase in ACTH

Cushing’s syndromeCushing’s syndrome secondary to pituitary adenomasecondary to pituitary adenoma increased ACTH, glucocorticoidsincreased ACTH, glucocorticoids round face, obesity, muscle wasting, poor wound round face, obesity, muscle wasting, poor wound

healing, osteoporosishealing, osteoporosis treated surgically to remove tumortreated surgically to remove tumor

MineralocorticoidsMineralocorticoids

Regulate electrolyte and water balanceRegulate electrolyte and water balance

Aldosterone:Aldosterone: most important mineralocorticoids in humansmost important mineralocorticoids in humans Increase reabsorption NaIncrease reabsorption Na++ from distal tubes and collecting ducts of kidney from distal tubes and collecting ducts of kidney

into plasmainto plasma Increase excretion KIncrease excretion K++ and H and H++ ↑ fluid volume ↑ fluid volume Increased aldosterone Increased aldosterone →→ hypokalemia, alkalosis hypokalemia, alkalosis Decreased aldosterone Decreased aldosterone →→ hyponatreuria, hyperkalemia hyponatreuria, hyperkalemia

MineralocorticoidsMineralocorticoids

Fludrocortisone is given orally to produce a mineralocorticoid effect. This agent:

increases Na+ reabsorption in distal tubules and increases K+ and H+ efflux into the tubules

acts, like most steroids, on intracellular receptors that modulate DNA transcription causing synthesis of protein mediators

is used with a glucocorticoid in replacement therapy.

Antagonists of AdrenocorticoidsAntagonists of Adrenocorticoids

Mineralocorticoid antagonistsMineralocorticoid antagonists

SpironolactoneSpironolactone (diuretic): inhibits the actions of (diuretic): inhibits the actions of mineralocorticoids; competitive inhibitor; mineralocorticoids; competitive inhibitor; androgen antagonistandrogen antagonist

Use:Use: treatment of primary aldosteronismtreatment of primary aldosteronism