Pituitary Adrenal Axis PDF

The pituitary-adrenal axis After this lecture the students should be able to: State the class of hormone to which cortisol belongs and identify where it is synthesized; Describe signaling events associated with steroid- based hormones Understand how ACTH release is regulated and discuss how...

The pituitary-adrenal axis After this lecture the students should be able to: State the class of hormone to which cortisol belongs and identify where it is synthesized; Describe signaling events associated with steroid- based hormones Understand how ACTH release is regulated and discuss how it regulates cortisol release; Identify the sites of action of cortisol and explain how cortisol exerts its effects Describe the consequences of cortisol excess and its deficiency and discuss the phenotypes manifested in Cushings syndrome and Addison’s disease The adrenal gland is a hybrid gland consisting of a cortex and a medulla. The hormones of the adrenal gland are important regulators of metabolism and serve an important role in adaptation to stress. Cortisol is a glucocorticoid and increases plasma glucose levels; deficiency can result in hypoglycemia. Because of the anti- inflammatory and immunosuppressive actions of adrenal corticosteroids, synthetic analogs are widely used in the treatment of disorders ranging from skin rashes to arthritis. Aldosterone is a mineralocorticoid, promotes salt and water retention by the kidney, critical for normal salt/water balance. The adrenal cortex also synthesizes and secretes androgenic steroids, which may be converted by peripheral tissue to testosterone. Although the primary product of chromaffin cells in the medulla is epinephrine, it also produces variable amounts of the epinephrine precursor norepinephrine. These catecholamines are distinct from the steroid hormones both structurally and functionally. capsule Products and Zonation of the AG The Adrenal Gland: Modulating our stress response  Steroid Hormones Ø All steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it. Ø All steroid hormones are lipid soluble thus are freely permeable to membranes so are not stored in cells; they leave cells shortly after synthesis. Ø Steroid hormones are carried in the blood complexed to specific binding globulins. e.g., Corticosteroid binding globulin transports cortisol Ø Enzymes which produce steroid hormones from cholesterol are located in mitochondria and SmER Ø In some cases a steroid is secreted by one cell and is converted to the active steroid by the target cell; for example cortisol  Sources of Cholesterol for Steroid Synthesis The amount of free cholesterol in the cell is maintained relatively constant: Complexed with protein for exit Stimulation - cellular synthesis of cholesterol from free acetate cholesterol steroid level synthesis esterified cholesterol level The cholesterol precursor comes from cholesterol LDL synthesized within the cell from acetate, from Stimulation cholesterol ester stores in intracellular lipid droplets or from uptake (cholesterol-containing low density lipoproteins).  Steroid Hormone Synthesis A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates. The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR), moving cholesterol from the outer membrane to the inner membrane where cholesterol is converted into pregnenolone by the enzyme, cytochrome P450 side-chain cleavage (P450scc; also called desmolase, or CYP11A1). This is a rate limiting, nonreversible step in the initiation of steroid biosynthesis. This step occurs in adrenal, ovary, and testis.  Extracellular lipoprotein acetate Cholesterol pool (CE) L HS T A AC ACAT = acyl CoA Free cholesterol cholesterol transferase HSL = hormone sensitive lipase Pregnenolone In the adrenal gland, pregnenolone can be converted into three different pathways, depending upon whether you want to make mineralcorticoids, glucocorticoids, or androgens Steroid Hormone  Adrenal Steroidogenesis Zona glomerulosa zona fasciculata zona reticularis (CYP17) (CYP17) 17a-hydroxylase lyase pregnenolone 17a-hydroxypregnenolone dehydroepiandrosterone 3b-hydroxysteroid dehydrogenase progesterone androstenedione 21-hydroxylase 11b-hydroxylase (CYP11B2) 18 hydroxylase/oxidase glucocorticoids mineralocorticoids (cortisol) (aldosterone) What determines which pathway is taken? Each step of the pathway is regulated by a specific enzyme. Different zones of the adrenal cortex have different relative activities of enzymes, resulting in different chemical reactions taking place. e.g., CYP17 not expressed in glomerulosa CYP11B2 (aldosterone synthase) only in glomerulosa zona fasciculata glucocorticoid: function The largest and most actively steroidogenic zone is the middle zona fasciculata producing the glucocorticoid hormone, cortisol….in the mitochondria and SmER Lipid droplet  Transport and Metabolism of Cortisol Cortisol is transported in blood predominantly bound to corticosteroid-binding globulin (CBG) (also called transcortin, binds 90%) , and albumin (binds 5% to 7%). The unbound (free; 3 – 5%) form of the hormone exerts biologic effects within target cells and feeds back on the pituitary and hypothalamus. The liver is the predominant site of steroid inactivation and conjugates 95% of active and inactive steroids with glucuronide or sulfate for excretion by the kidney. The circulating half-life of cortisol is about 70 minutes.  Mechanism of action Cortisol acts primarily through the GR (glucocorticoid receptor), which binds to GRE (glucocorticoid responsive element) and regulates gene transcription. In the absence of hormone, the GR resides in the cytoplasm in a stable complex with several molecular chaperones, including heat-shock protein 90 and cyclophilins. Cortisol-GR binding promotes dissociation of the chaperone proteins, followed by the following:  Rapid translocation of the cortisol-GR complex into the nucleus. Dimerization and binding to GREs near the basal promoters of cortisol-regulated genes. Recruitment of coactivator or co-repressor proteins, followed by covalent modification of chromatin (e.g., histone acetylation for activation; histone deacetylation for inactivation). A change (increase or decrease) in the assembly of the general transcription factors, leading to changes in the transcription rate of the targeted genes. Phosphorylation, followed by nuclear export and/or degradation of the GR, thereby terminating the signal.  Metabolic Effects of Cortisol Glucocorticoids are essential for life. If the adrenal cortex is removed or is not functioning, exogenous glucocorticoids must be administered or death will ensue. The actions of glucocorticoids are essential for gluconeogenesis, for vascular responsiveness to catecholamines, for suppression of inflammatory and immune responses, and for modulation of CNS function; catabolic and diabetogenic qualities. Glucocorticoids are essential for survival during fasting.  Metabolic Effects of Cortisol Glycogen Liver Glucose Glucose-P Glucose Amino Glucose Free fatty Protein acids precursors acids + Adipose Glycerol tissue Stimulate Plasma Muscle Inhibit Glucose Free fatty acids Amino acids Stimulates protein and triglyceride catabolism Stimulates “gluconeogenesis” in liver Inhibition of glucose uptake by body (insulin antagonism) but not by brain. Elevates blood glucose levels, “diabetogenic effect.” Nervous system becomes primary user of glucose during stress. Inhibits bone formation Inhibition of non-essential functions (reproduction; growth) Cortisol tames immune response It is prescribed to suppress inflammation and the immune system. Analogs of glucocorticoid are frequently used pharmacologically (e.g., as immunosuppressants in organ transplantations. When cortisol levels are high, many of the body's defense mechanisms against infection are inhibited. However, disruption of physiologic homeostasis leads to side effects such as alterations in water balance, weight gain, hypertension, muscle weakness, diabetes, and osteoporosis. These side effects are mediated through the genomic function of GR (i.e. through the activation of glucocorticoid response element [GRE]-mediated transcription).  Regulating the mineralocorticoid action of cortisol Cortisol can bind to the mineralocorticoid receptor (MR) with high affinity and activate the ‘incorrect’ set of genes….but it is transported in the inactive form (reversibly inactivated by, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)); the enzyme that converts it to the active form (11β- HSD1) is only present in tissues that express the GR, including liver, adipose, skin, and CNS. Thus, the mineralocorticoid receptor (MR) is free and available in aldosterone-responsive cells (e.g., distal convoluted tubule cells of the kidney) GC 11b-HSD2 MC tissues tissues 11b-HSD1 Active Inactive (cortisol, corticosterone) cortisone, 11-dehydrocorticopsterone Natural black licorice contains glycyrrhizic acid (GZA) which inhibits 11β-HSD2 and thereby increase the mineralocorticoid activity of cortisol leading to Na retention, spikes in blood pressure, muscle spasms and a disturbance of the acid-base balance zona fasciculata glucocorticoid: regulation  Regulation of glucocorticoid secretion by HPA axis centrally driven ACTH (Adrenocorticotropic hormone) response e.g. Rapid effects: StAR, HSL, SCC (desmolase) Stress! Longer-term effects: enzymes necessary e.g. hypoglycemia for cholesterol synthesis and LDL receptor Trophic effects: health of z. fasciculata and normal daily reticularis rhythm The suprachiasmatic nucleus and retina impose a circadian rhythm on CRH secretion, therefore ACTH secretion, therefore cortisol. Pulsatile release of CRH and ACTH, relative longer half life of cortisol (70 vs 10 mins) is reflected in the traces below. Cortisol (mg/dL) ACTH (pg/mL) Glucocorticoid regulation and function: Summary Inhibits synthesis transcription of CRH CRH release Inhibits synthesis of CRH receptor ACTH ACTH release tissue Consequence of action Figure 23-3: The control pathway for cortisol  Effects of altered glucocorticoid/steroid levels In hypocortisolism (e.g., primary adrenal insufficiency, Addison's disease), there is hypoglycemia. In hypercortisolism (e.g., Cushing's syndrome), there is hyperglycemia If pituitary lesion If excess ACTH or no ACTH (chronic stress, or pituitary tumor (Cushing disease)), or deficiency in cortisol feedback fasciulata and reticularis atrophy Enlarged adrenals (ACTH acts as a trophic factor; angiotensin II and high K trophic for glomerulosa) Excess steroids No cortisol; dependency on exogenous glucocorticoids  Effects of altered glucocorticoid levels: Adrenal Hyperplasia impaired feedback Excess CRH and ACTH Hyperplastic Reduced adrenal cortisol release Excess secretion and symptoms 21-hydroxylase deficiency symptoms: varying degree of virilism in females including hirsutism and clitoral hyperplasia; precocious puberty in boys Also, when the HPA axis is over-stimulated because of stress, and if the body cannot keep up with the demand for cortisol, or if there is any other steroidogenic enzyme block, excess ACTH might be shunted into the androgen production pathway. Effects of altered glucocorticoid levels: Cushing syndrome Cushing’s disease is hypercorticism (increased glucocorticoid production) caused by a pituitary basophilic adenoma. Cushing’s syndrome refers to the consequences of increased plasma glucocorticoid concentration from any source. ACTH and cortisol measurements discriminate between ACTH-dependent and independent causes. Exogenous cause Endogenous causes Overproduction of cortisol Taking medicines Pituitary tumor Adrenal tumor Other unknown containing (Cushing’s disease) glucocorticoids independent dependent independent ACTH Two primary consequences 1. Salt and water-retention with renal loss of K+ results in “moon face”. The fluid-retention eventually leads to cardiac hypertrophy due to prolonged hypertension. There is often peripheral oedema, due to the glucocorticoid-induced diabetes. This type of diabetes is typically resistant even to large doses of insulin. 2. Catabolism causes muscle wasting, fat accumulation, osteoporosis with kyphosis, buffalo hump, and fractures. The skin is thin with ulcers and red stirrer, and there is poor wound healing. There is impaired fibrocyte formation and capillary resistance. Effects of altered glucocorticoid levels: Cushing syndrome Effects of altered glucocorticoid levels: Addison disease a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroid hormones (glucocorticoids and often mineralocorticoids). Symptoms Overproduction of ACTH due to decreased negative feedback by cortisol Skin hyperpigmentation (excessive ACTH as well as other products of the parent precursor, POMC, lead to increases in a and g forms of melanocyte-stimulating hormone, MSH) Glucocorticoid deficiency symptoms: predisposition to hypoglycemia, hypotension, changes in mood and personality, muscle weakness, anemia, decreased GI motility and appetite (weight loss), decreased water clearance Mineralocorticoid deficiency symptoms: loss of Na (craving for salt) and fluids and retention of K (hyperkalemia), hypotension, muscle fatigue and pain ( due to increased extracellular K)