KEY STEPS

• ATP binds myosin, which causes its release from actin.
• ATP hydrolysis causes the myosin head to rotate.
• High energy myosin binds ATP (forms the cross-bridge).
• Phosphate release initiates the power stroke.

MYOFIBRIL INTERNAL HISTOLOGY

Thick filaments

• Form from myosin
• The A band refers to the length of the thick filaments, “think “A” for d-a-rk – they are aniosotropic (or birefringent) in polarized light.
• H Zone is a zone of only thick filaments.
• M line bisects the A band.

Thin filaments

• Form from actin
• The I band is the region along the thin filaments (between the thick filaments).
• Think “I” for L-i-ght – they are “isotropic” (do not alter polarized light).

Z disks

• Transverse bands at the ends of the thin filaments.

Sarcomere

• The contractile unit of the myofibril.
• Comprises the area between the Z-disks.

• The thin filament slides towards the H zone.
• The (+) end attaches to the Z-disc sarcomere; the (-) end of the filament points toward the H zone.

Actin

• Spherical molecules joined in pairs of strands (like beads on a string). It is referred to as F-actin for filamentous actin, and comprises a polymer of G-actin monomers that are arranged in a double helix.
• There are myosin binding sites on actin and an ATPase site, an ATP-splitting site.

Tropomyosin

• Threadlike strands

Troponin

• Protein complexes that bind tropomyosin, actin, and also calcium (show their calcium-binding sites).

THICK FILAMENTS: DETAILS

• Comprise myosin molecules (technically myosin II), which form a golfclub shape, and comprise two heavy chains and two light chains.
• The head forms from the heavy chain and contains the actin-binding site.

The “cross-bridge” is the bond between actin and myosin.

THE HUXLEY SLIDING-FILAMENT MODEL

The rigor state.

• The myosin head is bound to the thin filament.
• Calcium is bound to troponin.
  • Calcium binding to troponin allows myosin access to its binding site on actin.

ATP induces release of actin.

• Myosin has ATP bound to its head.
• The actin molecules are separated from (no longer bound to) the myosin.
• ATP is required to move out of the rigor state.
• If ATP is absent, which occurs after death, rigor will persist, called rigor mortis.

ATP is hydrolyzed to ADP and Inorganic phosphate (Pi).

• The myosin head rotates on the neck: it is now “cocked”: it’s in its high-energy state.
• The “cocked” state causes the thin and thick filaments to again bind via their cross-bridge.
• ADP and inorganic phosphate (Pi) are still bound to the myosin head.

Pi release initiates the power stroke for the myosin head to release its energy.

• Accordingly, the thin filament begins its slide.

The myosin returns to its uncocked, low energy state.

• At some point after the power stroke, ADP is released.
• Note that this is an area of intertextual variation, some authors instead write that ADP is released at the same time as phosphate to initiated the power stroke.

ATP GENERATION: 3 KEY MEANS

Direct phosphorylation:

• Creatine phosphate (a high-energy molecule stored in muscle cells) couples with ADP to make ATP and creatine.
• Creatine kinase catalyzes the reaction.
• As a corollary, creatine kinase is the best marker for muscle disease; it lies within muscle cells, for instance on the inner mitochondrial membrane, myofibrils, and sarcoplasm, and muscle injury releases it into the serum. Thus, muscle diseases are commonly associated with elevated creatine kinase levels.

Anaerobic glycolysis

• Nets 2 ATP molecules.
• Each glucose molecule is broken down into pyruvic acid molecules and ATP, but the pyruvic acid converts to lactic acid.
• Strenuous anaerobic exercise results in lactate build-up, which causes pain.

Aerobic respiration (which occurs in the presence of oxygen)

• Glucose is entirely broken down within the mitochondria to yield carbon dioxide, water, and large amounts of ATP.
• As a corollary, we see that in the presence of oxygen, cells can maximize ATP production.

KEY PRINCIPLES:

• Insulin and glucagon are regulatory hormones that coordinate the storage and release of nutrients into the body
  • Insulin, the “hormone of excess,” promotes the storage of glucose, fatty acids, and amino acids
  • Glucagon, the “hormone of starvation,” promotes formation of glucose and fatty acids

KEY TERMS

• Glycogenolysis is the process by which glycogen is broken down to form glucose
• Gluconeogenesis is the process by which glucose is formed from non-carbohydrate substances (i.e., not glycogen)
• Glycogenesis is the formation of glycogen from glucose (so, the opposite of glycogenolysis)
• Glycolysis is the breakdown of glucose (which generates ATP, and is addressed in detail, elsewhere)

INSULIN

Actions

Insulin lowers blood glucose, amino acid, fatty acid, and potassium concentrations.

• Moves these substances out of the blood and into the cells.
• Promotes their storage and prohibits further synthesis.
  • Glucose is stored as triglycerides and glycogen within adipose (fat) and skeletal muscle tissue.
  • Within the liver, insulin prohibits glyconeogensis (glucose formation), and promotes glycolysis (glucose breakdown).
  • Insulin increases the storage of fatty acids in adipose tissue, and inhibits lipolysis.
  • Insulin promotes amino acid and protein uptake by skeletal muscle tissue and increases protein synthesis; it inhibits protein degradation.
  • Insulin increases sodium-potassium pump activity, which increases cellular potassium uptake.

Clinical Correlation:

A consequence of insulin insufficiency (Type I diabetes) is hyperkalemia, because potassium shifts to the extracellular fluid. Hyperkalemia presents with weakness, chest pain, and difficulty breathing.

Insulin Release

• Stimulation of pancreatic beta cells release insulin, which then enters the hepatic portal system; recall that the hepatic portal system carries venous blood from the digestive organs.
• From the hepatic portal system, insulin is carried to the heart and enters the systemic circulation to be delivered to its target tissues, which, as we indicated above, primarily include the liver, adipose, and skeletal muscle tissue.

Stimuli for Release

In general, insulin is released after a meal.

• Increased blood glucose (most important), fatty acid, and amino acid concentrations
• Increased gastric secretion, particularly of incretins(i.e., GIP and GLP-1)
• Vagal stimulation

Inhibition of Release

• Low blood glucose concentration
• Increased fasting and/or exercise
• Catecholamines (norepinehrine and epinephrine),
• Somatostatin; recall that somatostatin is released from the delta cells of the pancreas.

GLUCAGON

Actions

• Raises blood glucose and fatty acid concentrations via stimulation of glucose and fatty acid mobilization in the liver.
• Promotes gluconeogenesis, glyconeogenesis, and glycogenolysis, which leads to increases in blood glucose concentrations.
• Increases lipolysis and decreases triglyceride storage, so that fatty acids are released into the blood stream.

Glucagon Release

• Pancreatic alpha cells release glucagon, which, like insulin, enters the hepatic portal system;
• Primary target tissue is the liver itself, which we saw in our previous diagram.
• Released between meals or upon ingestion of proteins.

Stimuli for Release

• Low blood glucose concentrations,
• Increased blood protein levels, and
• Increased gastric secretions, particularly of CCK (which, as you may recall, is itself released in response to protein ingestion).
• Catecholamines; this makes sense as part of the “fight or flight” response, a time when our tissues, particularly skeletal tissues, would need all available sources of fuel.

Inhibition of Release

• High levels of blood glucose and fatty acid concentrations
• Elevated levels of insulin
• Somatostatin
  • Somatostatin inhibits both insulin and glucagon release; thus, these three pancreatic endocrine secretions co-ordinate to maintain homeostatic blood nutrient concentrations.

PANCREATIC ENDOCRINE CELLS

• Comprise the Islets of Langerhans: each of which is a cluster of 4 endocrine cell types, whose products are ultimately secreted into the hepatic portal blood and delivered to the liver.
• A key function of pancreatic endocrine cells is to maintain basal blood glucose concentration via regulated storage and release: glucose is a major source of energy for the body.
• In order to maintain homeostatic blood glucose concentrations, the islet cells engage in communication via neural, hormonal, and cell-to-cell signaling.

Pancreatic endocrine cell types:

Alpha cells

• Comprise approximately 20% of the islet cells
• They secrete glucagon, which increases blood glucose concentrations between meals.

Beta cells

• Comprise approximately 65% of the islet cells
• They secrete insulin, which lowers blood glucose concentrations after a meal.

Delta cells

• Comprise approximately 10% of the islet cells
• Secrete somatostatin, which inhibits insulin and glucagon secretion to moderate their effects on blood glucose concentrations.

F cells

• Are rare
• They secrete pancreatic polypeptides, whose specific functions are uncertain.

Beta cell insulin secretion.

• Beta cells release insulin in response to multiple stimuli, but glucose is the primary stimulus.

Step 1:

• Glucose diffuses into the beta cell via GLUT – 2 receptors;

Step 2:

• Within the cell, glucose is phosphorylated by the enzyme glucokinase.

Step 3:

• Oxidation of phosphorylated glucose produces ATP.

Step 4:

• ATP closes potassium channels, trapping potassium inside the cell.
• This depolarizes the cell membrane.

Step 5:

• In response to depolarization, calcium channels open, and the intracellular calcium concentration increases.

Step 6:

• This triggers exocytosis of insulin-containing vesicles.

Bear in mind that the beta cell response to fatty acids and proteins is similar, though not identical.

As discussed in detail elsewhere, insulin is released into the nearby capillaries, drains into the hepatic portal system, and, eventually, enters systemic circulation to reach its target tissues.

Clinical Correlations:

Insulin-dependent, aka, Type I diabetes

• Destruction of beta cells (often by autoimmune disorders) causes insufficient circulating levels insulin; thus, carbohydrate, protein, and fat metabolism is inhibited.
• Because Type I diabetes is due to insulin insufficiency, insulin replacement therapy is the primary treatment to normalize blood nutrient concentrations.

Insulin-resistant, aka, Type II diabetes

• Down-regulation of insulin receptors on target tissues, specifically in the liver, skeletal, and adipose tissues, inhibits metabolism of carbohydrates, protein, and fat.
• Despite normal, or even elevated, levels of insulin, the target tissues cannot respond as usual; thus, treatment includes insulin receptor sensitizers (in addition to insulin therapy).

Hormonal regulation of extracellular calcium and phosphate concentrations by the parathyroid glands.

Key Principles

Free calcium participates in various cellular processes, including:

• Skeletal, cardiac, and smooth muscle contraction
• Nerve conduction
• Blood clotting
• Bone and tooth formation
• Enzyme activation and deactivation

Phosphate is a part of ATP

• Participates in cellular metabolism
• Plays a role in enzyme activation and deactivation

Storage and Release:

Calcium and phosphate are stored within hydroxyapatite crystals of bone

• When bone is resorbed, calcium and phosphate are released into the extracellular fluid
• Calcium and phosphate levels are regulated by the same hormones:
  • Parathyroid hormone, which is secreted by chief cells of the parathyroid glands
  • Vitamin D (in activated form)

(The physiologic role of calcitonin, a hormone released by the thyroid gland in response to increased calcium concentrations, is as of yet uncertain, and, therefore, omitted in this tutorial.)

PARATHYROID HORMONE PATHWAYS:

In response to lowered extracellular calcium concentration, the parathyroid glands secrete parathyroid hormone (PTH).

Bone:

• In bone, episodic, transient binding of parathyroid hormone causes an increase in new bone synthesis
• Prolonged exposure to parathyroid hormone promotes resorption of old bone, and, therefore, the release of calcium and phosphate into extracellular fluid

Clinical consequences of these dichotomous effects:

• Osteoporosis, which is characterized by loss of bone density, can be treated with intermittent PTH administration
• Continuous release of PTH in individuals with hyperPARAthyroidism causes excessive bone resorption

Kidneys:

• Increased calcium reabsorption in the distal convoluted tubule of the nephrons
• Decreased phosphate reabsorption in the proximal convoluted tubule, which leads to phosphaturia, an increase in phosphate in the urine
  – This action is important because, otherwise, reabsorbed phosphate would complex with the reabsorbed calcium, which would negate its physiologic effects in the body.

PTH STIMULATES RENAL ACTIVATION OF VITAMIN D

Kidney

• Vitamin D acts increases renal reabsorption of both calcium and phosphate

Small Intestine

• Vitamin D increases calcium and phosphate reabsorption

Bones

• Vitamin D works with parathyroid hormone to facilitate skeletal remodeling, which requires both synthesis and resorption of bone.

Clinical correlation:

Vitamin D deficiency in children causes rickets, in which skeletal development is impaired, the bones are weak, and, consequently, growth is often stunted.

System-wide consequences of calcium imbalances:

Hypocalcemic individuals experience hyperreflexia, muscle twitching and cramping, numbness and tingling

• Trousseau’s sign, characterized by involuntary hand and feet spasms, carpopedal spasms, which can be provoked by the examiner by inflating a blood pressure cuff to cause prolonged brachial artery occlusion.
• The Chvostek sign, characterized by hyper excitable facial muscle twitching in response to tapping the facial nerve.

Hypercalcemic individuals experience hyporeflexia, muscle weakness, lethargy, and, polyuria.

THYROID GLAND PRODUCTS

T3 (full name, triiodothyronine)

• T3 is more biologically active.

T4 (full name, thyroxine, aka, tetraiodonthyronine).

• The thyroid produces T4 in greater quantities; so, target tissues to need to use 5′ iodinase convert T4 to T3.

THYROID HORMONE SYNTHESIS

• Synthesis occurs both intra- and extracellularly.

Step 1:

• Thyroglobulin is synthesized in the follicular epithelial cell and transported to the lumen.
  • Thyroglobulin is a tyrosine-rich protein.

Step 2:

• The “i-trap,” which is a sodium-iodine co-transporter, pulls iodiDe into the cell from the capillaries.
  • Iodide is a trace element that does not occur naturally in the body, so it must be consumed in the diet.

Step 3:

• Oxidization of iodiDe to iodiNe by the enzyme thyroid peroxidase.

Step 4:

• Organification, also driven by thyroid peroxidase, to combine iodine with the tyrosine of luminal thyroglobulin;
• As a result of organification, two thyroid hormone precursors form and attach to thyrogobulin:
  • MIT (full name, monoiodotyrosine)
  • DIT (full name, diiodotyrosine)

Step 5:

• Thyroid peroxidase drives coupling reactions:
  • Two DIT molecules combine to form T4.
  • One DIT molecule combines with one molecule of MIT to form T3.
• Ultimately, some MIT and DIT will be “left over,” and remain bound to thyroglobulin with T3 and T4 in the colloid.
• Recall that, as we learned earlier, T4 is produced in larger quantities.

Step 6:

• Thyroglobulin, along with thyroid hormone and its precursors, are endocytosed to the follicular cell.

Step 7:

• Upon glandular stimulation, MIT and DIT are released from thyroglobulin; they remain within the cell to be recycled in the synthesis of new thyroglobulin.
• Though omitted for simplicity, MIT and DIT are deiodinated
  • IoDide returns to the pool of iodide within the cell.
  • Tyrosine molecules are recycled in the synthesis of new thyroglobulin molecules.
• T3 and T4 are delivered to the systemic circulation to reach their target tissues.
• Most T3 and T4 travels in the blood bound to thyroxine-binding globulin (a carrier protein); only free T3 and T4 are physiologically active.

Overview

• Growth hormone, aka, somatotropin, (somatotrophin) is secreted by anterior pituitary cells called somatotrophs.
• Somatotrophs make up more than half of the anterior pituitary, and growth hormone is the most abundantly secreted anterior pituitary hormone.
• Growth hormone is responsible for growth of almost all tissues, whether directly or indirectly via insulin-like growth factor 1 (IGF-1).
• Growth hormone secretion is pulsatile, and is highest during sleep.
• Growth hormone levels vary throughout life; they begin to fall after adolescence.
• Negative feedback loops regulate growth hormone secretion.

Growth Hormone Physiology

• First, we draw the hypothalamus and pituitary gland.
• Neurosecretory cells originate in the arcuate nucleus of the hypothalamus, and their axons terminate on capillaries of the hypothalamic-pituitary portal system.
• Within the anterior pituitary, there are various collections of endocrine cells;
  – We label the somatotrophs with an S, and show the nearby capillaries that deliver hormone products to the blood supply.

Growth Hormone Release

• The hypothalamus secretes growth hormone releasing hormone (GHRH) into the neurosecretory cells.
• When it reaches the anterior pituitary, GHRH stimulates somatotropin release of Growth Hormone (GH), which then travels in the blood to tissues throughout the body.

Growth Hormone Effects

• Growth effects: it increases cell growth, proliferation, and differentiation throughout the body.
• Direct effects on growth:
  – Increases bone length and muscle mass (growth hormone promotes protein deposition).
• Indirect effects on growth:
  – Diabetogenic effects: growth hormone increases glycogen breakdown in the liver to increase blood glucose, which can be used as fuel by growing body tissues.
  – Growth hormone also increases insulin-like growth factor 1release from the liver, which in turn promotes growth and differentiation of various tissues.

Be aware that IGF-1 is sometimes referred to as somatomedin-C

– Glucose-sparing effects: it increases lipolysis, and decreases glucose uptake by skeletal muscle and adipose tissue, which frees up energy for growth of tissues.

Growth Hormone Regulation

• Key regulators:
  – At the hypothalamus:
  Sleep, hypoglycemia, and stress trigger the release of growth hormone releasing hormone.
  Age and obesity are associated with reduced GHRH release, and, via negative feedback loops, glucose, IGF-1, and growth hormone also reduce GHRH release.
  – At the level of the anterior pituitary:
  Release of growth hormone is inhibited by growth hormone inhibitory hormone (aka, somatostatin, which is released by the hypothalamus), and via negative feedback signals from IGF-1 and Growth hormone (notice that IGF-1 and growth hormone provide negative feedback at both the hypothalamus and the anterior pituitary).

• Additional factors that promote and inhibit growth hormone secretion:
  – Stimulates Secretion:
  Growth hormone releasing hormone
  Decreased blood glucose
  Decreased blood free fatty acids
  Increased blood arginine (an amino acid)
  Protein deficiency and starvation
  Stress and excitement (including a variety of experiences, including exercise and trauma)
  Testosterone and estrogen
  Deep sleep
  Ghrelin, which is a growth hormone secretagogue (GHS) that is produced mainly in the stomach.

– Inhibits Secretion:
Growth hormone inhibiting hormone (aka, somatostatin)
Increased blood glucose
Increased free fatty acids
Exogenous growth hormone
Insulin-like growth factor 1 (via negative feedback)
Aging
Obesity

Pause to recognize that low blood glucose, low levels of free fatty acids, and increased levels of amino acids in the blood stimulate growth hormone release, which ultimately reverses each of these states to maintain homeostasis.

Growth Hormone Pathologies

Growth Hormone Defects

Growth hormone deficiency

• Characterized by low levels of growth hormone and IGF-1
  – If there is not enough growth hormone to trigger its production, IGF-1 will necessarily be low.
• Isolated growth hormone deficiency is often due to defects in the GH1 gene, which is responsible for growth hormone production.
• In other cases, growth hormone deficiency is an aspect of general hypopituitarism, in which other anterior pituitary hormones are also low.
• Patients can be treated with recombinant human growth hormone.
  Growth hormone insensitivity is characterized by normal or high levels of growth hormone, and low levels of IGF-1.
• This is the result of growth hormone receptor defects
  – May be hereditary, as in Laron Syndrome.
  – May acquired as a result of malnutrition, liver disease, diabetes, growth hormone receptor antibodies, or other pathologies.
• Patients can be treated with recombinant IGF-1.
• In Children:
  – Linear growth is slow (sometimes called pituitary dwarfism).
• Children often have delayed puberty, with small gonads and genitalia (micropenis).
• In Adults:
  – Body composition changes, including reduced muscle and bone mass, and increased fat mass.
  – Increased risk of cardiovascular disease (including left ventricular dysfunction and hypertension), and are more likely to develop insulin resistance.
  – Additionally, reduced exercise capacity, lethargy, and depression contribute to a lower quality of life in these patients.

Growth Hormone Excess

• Excessive section of growth hormone leads to elevated growth hormone and IGF-1
  – Be aware that prolactin is also often elevated.
• In both children and adults, the most common cause of growth hormone hypersecretion is an adenoma in the anterior pituitary.
  – Treatment often requires tumor removal.
• In Children: Gigantism
  – Growth hormone hypersecretion occurs prior to fusion of the epiphyseal plates.
  – This causes accelerated linear growth, and children are taller than their age/sex-matched peers; delayed puberty is also likely.
• In Adults: Acromegaly
  – Growth hormone hypersecretion occurs after epiphyseal plate fusion.
  – Thus, linear growth can’t occur, but bone deformation, soft tissue swelling, and enlargement of facial features, hands, and feet are common.
  – Patients are more likely to experience sleep apnea, diabetes, cardiovascular disease, arthropathy, carpal tunnel, headaches and visual disturbances due to tissue swelling and metabolic changes.

Posterior lobe of the pituitary gland

• The hypothalamus regulates the pituitary’s endocrine functions via hormonal and neural mechanisms.
• The pituitary gland, aka, hypophysis, divides structurally and functionally into the:
• Anterior lobe and posterior lobe (aka neurohypophysis), which directly connects to the hypothalamus.
• Direct connection allows the hypothalamus to communicate with the posterior lobe via neural connections – the posterior lobe is derived from neural tissue (hence its name “neurohypophysis”).
• Infundibulum connects hypothalamus and posterior lobe.
• Posterior lobe does not synthesize hormones but rather stores and secretes neurohormones synthesized by the hypothalamus.

Pathway:

Hypothalamo-hypophyseal tracts:

• Paraventricular and supraoptic nuclei of the hypothalamus house the cell bodies of neurosecreting cells.
• Neurosecretory cell traveling from the hypothalamus to the posterior lobe.
• Cell body synthesizes and packages neurohormones in vesicles
• Axon delivers the vesicles to its terminal in the posterior lobe, where it stored until its release is signaled.
• When signaled to do so, the vesicles release the neurohormone.
• The hormone then enters the venous blood so that it can travel within the systemic circulation to reach its target organs.

Two hormones secreted from the posterior lobe of the pituitary gland.

Anti-diuretic hormone, ADH, is released in response to low blood pressure and/or water volume contraction.

• ADH induces vasoconstriction, which counteracts low blood pressure; this explains its alternative name, vasopressin.
• ADH also acts on the distal nephron tubules of the kidneys to increase water reabsorption, which counteracts water volume contraction.
• Central diabetes insipidus is caused by defects in the hypothalamic nuclei or in the mechanisms of axon transport. As a result, ADH is not secreted by the posterior pituitary, and individuals produce large quantities of dilute urine.

Oxytocin

• Smooth muscle contraction in lactating mammary glands and uterus.
• In the breast, oxytocin promotes myoepithelial cell contraction and milk ejection.
• Suckling promotes oxytocin release to facilitate breastfeeding.
• In the uterus, oxytocin induces rhythmic myometrium contractions during parturition (to expel the fetus) and orgasm.
• Stretch receptors in the vagina trigger its release.

Many authors report a possible, but uncertain, role for oxytocin in the male sexual response, as well.
Oxytocin is also thought to enhance emotional and behavioral responses, particularly in romantic and mother-child interactions; however, these relationships can be difficult to ascertain, and are omitted, here.

Key Principles

• The hypothalamus regulates the endocrine functions of the pituitary gland via hormonal and neural mechanisms; as we’ll see, the hypothalamus can either stimulate or inhibit the the pituitary gland.
• The pituitary gland (aka, hypophysis) is structurally and functionally divisible into two lobes.
  • The anterior lobe aka, adenohypophysis is derived embryologically from the foregut; it receives hypothalamic regulating signals via the hypothalamic-hypophyseal portal veins.
  • 6 tropic hormones are secreted by the anterior pituitary lobe; “tropic” means they act on target tissues to stimulate release of other endocrine products.
  • The posterior lobe aka, the neurohypophysis, receives hypothalamic signals via neural connections. As we’ll learn elsewhere, the posterior lobe is derived from neural tissues.

Anatomy

• Hypothalamus is superior to the pituitary gland
• Pituitary gland comprises anterior and posterior lobes
• Infundibulum, aka, pituitary stalk, which connects the hypothalamus to the pituitary gland.

Pathway:

• Cell bodies of hypothalamic neurons send axons inferiorly towards the pituitary gland.
• Axons deliver hypothalamic hormones to the portal blood vessels
• Hypothalamic-hypophyseal portal blood vessels deliver blood and hormonal signals from the hypothalamus to the pituitary gland (hypophysis).
• The the primary capillary plexus forms at the base of the hypothalamus (specifically, at the median eminence); it arises from the superior hypophyseal artery and drains, via portal vessels, inferiorly to the secondary capillary plexus, which bathes the endocrine cells of the anterior pituitary lobe.
• The secondary capillary plexus delivers neurohormones that stimulate or inhibit hormonal secretion by the nearby anterior lobe endocrine cells.
• Upon secretion, the anterior lobe hormones drain into systemic venous return to the heart; from here, they circulate within the systemic arterial blood to reach their target tissues.

Anterior Lobe Hormones:

FLATPiG

• Follicle-Stimulating hormone
• Lutenizing hormone
• Adrenocorticotropic hormone
• Thyroid-stimulating hormone
• Prolactin
• Growth hormone

CRH (corticotropin-releasing hormone)

• Stimulates the corticotrophs of the anterior pituitary lobe to release ACTH (adrenocorticotropic hormone)
• ACTH travels in systemic blood to reach the cells of the adrenal gland cortex. As we’ll discuss elsewhere, ACTH causes the adrenal cortex to secrete its own endocrine products.

GHRH (growth hormone-releasing hormone) stimulates somatotrophs of the anterior lobe to release growth hormone.

• Growth hormone has widespread metabolic effects in the body, particularly in the musculoskeletal system.
• Somatostatin (aka, growth hormone-inhibiting hormone), inhibits growth hormone secretion from the anterior lobe endocrine cells.

GnRH (gonadotropin-releasing hormone)

• Stimulates gonadotrophs in the anterior pituitary lobe to secrete FSH (follicle-stimulating hormone) and LH (luteinizing hormone), which travel in the bloodstream to act on gonadal cells (aka, ovarian and testicular cells) (details regarding these hormonal pathways are discussed elsewhere).

Thyroid-releasing hormone

• Released from the hypothalamus and triggers thyrotrophs to secrete thyroid-stimulating hormone, which stimulates endocrine cells of the thyroid gland.

PRH (prolactin-releasing hormone)

• Stimulates lactotrophs (aka, mammotrophic cells) of the anterior lobe to secrete prolactin, which triggers mammary gland growth and milk production in females.
• Indicate that PIH (prolactin-inhibiting hormone, aka, dopamine) inhibits the release of prolactin.
• Bromocriptine (a dopamine agonist) is used to treat prolactinomas (prolactin-secreting tumors).

As always, be aware that we’ve simplified the hormonal pathways and their effects, for clarity. Separate tutorials address the regulatory feedback mechanisms that govern the secretion of anterior lobe hormones.

Overview

• Adrenal cortex hormones, which are steroid hormones that regulate water and salt balance, blood sugar, and sexual characteristics, among other actions.
• Production of these hormones occurs in the mitochondria and smooth endoplasmic reticulum, and requires several enzymes, most of which belong to the family of cytochrome P-450 oxidases.
• As we’ll see, some key enzymes are only present in specific layers, which is why the layers produce different hormones.
• Adrenal capsule and cortex sublayers:

  – The zona glomerulosa, which produces mineralocorticoids.
  – The zona fasciculata, which produces glucocorticoids.
  – The zona reticularis, which produces androgens.

Pathways

• Begin at the top of the diagram with cholesterol, which is the precursor for all steroid hormones.
  – The adrenal gland can synthesize cholesterol, but the primary source of cholesterol is circulating LDL.
• Show that cortisol entry into adrenocortical cell mitochondria is facilitated by a transport protein called the steroidogenic acute regulatory protein – StAR.
• Show that cholesterol side chain cleavage cleaves cholesterol to form pregnenolone.
  – This step occurs in all layers of the adrenal cortex, and is upregulated by ACTH.

• From here, the pathway depends on the available enzymes.

We’ll first follow the pathway that leads to the production of aldosterone, the primary mineralocortioid, in the zona glomerulosa.

• So, show that pregnenolone is oxidized by 3 beta-hydroxysteroid dehydrogenase (3B-HDS) to form progesterone.

• Be aware that 3 beta-hydroxysteroid dehydrogenase, which plays a role in each layer of the adrenal cortex, is the only non-P-450 enzyme we’ll see in this diagram; we’ll come back to this point, later.

• Next, show that, within the zona glomerulosa, 21 alpha-hydroxylase converts progesterone to 11-deoxycortisterone (DOC), which is a weak mineralocorticoid.

• Then, 11 beta-hydroxylase converts 11-deoxycorticosterone to corticosterone.

• Lastly, show that aldosterone synthase, which is only present in the zona glomerulosa, converts corticosterone to aldosterone, the main mineralocorticoid.

• Show that angiotensin II facilitates aldosterone production in both early and late stages of aldosterone synthesis: like ACTH, it increases cholesterol side chain cleavage enzyme activity, and, it uniquely increases the activity of aldosterone synthase.
• Be aware that elevated potassium also increases aldosterone synthesis.

Now, let’s learn about cortisol production in the zona fasciculata.

• First, return to progesterone, and show that, in the presence of 17 alpha-hydroxylase, which is present in the zona fasciculata, progesterone is converted to 17-hydroxyprogesterone.

• Pause and show another pathway to 17-hydroxyprogesterone formation:
  – Return to pregnenolone, and show that 17 alpha-hydroxylase converts it to 17-hydoxypregnenolone, which, in the presence of 3 beta-hydroxysteroid dehydrogenase, is converted to 17-hydroxyprogesterone!

• Next, show that, in the presence of 21 alpha-hydroxylase, 17-hydroxyprogesterone is converted to 11-deoxycortisol.

• Then, show that 11 beta-hydroxylase adds a hydroxl to 11-deoxycortisol to produce cortisol, the primary glucocorticoid.

Finally, let’s see the pathway for adrenal androgen biosynthesis.

• Return to 17-hydroxypregnenolone, and show that, in the presence of 17 alpha-hydroxylase, it is converted to dehydroepiandrosterone (DHEA).
  – Be aware that some texts show this step occurring via 17,20 desmolase, aka, 17,20-lase; however, because these enzymes are encoded by the same gene as 17 alpha-hydroxylase, we can consider them to be the same enzyme for simplicity.

• Next, show that DHEA is converted to Androstenedione (A4)by 3 beta-hydroxysteroid dehydrogenase.

• Pause to show another pathway to A4:
  – 17-hydroxyprogesterone, which we saw in the pathway to cortisol biosynthesis, can be converted to androstenedione by 17 alpha-hydroxylase.

• Show that androstenedione is a precursor to testosterone, which is only minimally produced by the adrenal glands.

Sex steroids in the Peripheral Tissues

• Relatively weak adrenal androgens are converted to stronger sex hormones in the peripheral tissues:
  – Androstenedione and testosterone are converted to estroneand estradiol, respectively, via aromatase.
  – Testosterone is converted to dihydrotestosterone (DHT) via 5 alpha-reductase.

• Be aware that, although the adrenal glands are not the primary source of androgens in adult males, they are a significant source of androgens in children and women.

Key Enzymes

• 3 beta-hydroxysteroid dehydrogenase, which we indicated is involved in the production of all three hormone groups (mineralocorticoids, glucocorticoids, and androgens).
  – Non-P-450 enzyme.

• The rest of the enzymes we’ll show are P-450 enzymes and the gene names for each of these enzymes (some texts refer to them this way).

• Cholesterol side-chain-cleavage, aka, P-450SCC, gene name CYP11A1.
  – Recall that this enzyme was involved in the very early steps of steroid hormone biosynthesis, so it is a rate-limiting enzyme for all steroid hormones.
  – Be aware that this enzyme is sometimes called cholesterol desmolase.

• 11 beta-hydroxylase, aka, P-450-C11, gene name CYP11B1.
  – Notice that this enzyme is active in the formation of both aldosterone and cortisol, but not the androgens.
  – Another way to think of this is that this enzyme is only present in the zona glomerulosa and zona fasciculata.

• 17 alpha-hydroxylase, aka, P450-C17, gene name CYP17.
  – This enzyme is active in the production of cortisol and androgens, but not in the production of aldosterone
  – 17 alpha-hydroxylase is not significantly present in the zona glomerulosa.

• 21 alpha-hydroxyalse, aka, P-450-C21, gene name CYP21A2.
  – Notice that this enzyme is involved in the production of aldosterone and cortisol.

• Aldosterone synthase, aka, P-450-Aldo, gene name CYP11B2.
  – Recall that this enzyme is only present in the zona glomerulosa, and is responsible for the final steps of aldosterone synthesis.

Enzyme Deficiencies

• Generally speaking, when one enzyme is absent, its downstream hormone products are not synthesized, but upstream precursors and, therefore, other hormones, are produced in excess.
  – We’ll address the causes and consequences of these deficiencies elsewhere (i.e., congenital adrenal hyperplasia).

• Deficiency of 11 beta-hydroxylase:
  – Both aldosterone and cortisol levels are decreased.
  – Upstream hormones, such as 11-deoxycortisol, are increased.
  – 11-deoxycortisol is a weak mineralocorticoid, but show that, in excessive quantities, it can cause hypertension, hypokalemia, and reduced renin activity (remember that blood pressure follows aldosterone).
  – Androgen production is increased due to excessive quantities of “upstream” hormones in the shared pathway.
  In females, increased androgen production leads to virilzation (the development of “masculine” characteristics, like increased muscle mass and body hair); in male children, look for precocious puberty.

• Deficiency of 17 alpha-hydroxylase:
  – Decreased cortisol and androgen production, and, therefore, increased mineralocorticoid production.
  – Increased mineralocorticoid production (i.e., DOC) leads to hypertension and hypokalemia.
  – Congenital 17 alpha-hydroxylase deficiency produces ambiguous genitalia with undescended testes in males, and in females, lack of secondary sex characteristics.

• Deficiency of 21 alpha-hydroxylase:
  – Reduced mineralocorticoid and cortisol production.
  – Thus, potassium levels, renin action, and androgen levels will be elevated, but blood pressure will be low due to decreased mineralocorticoid action.
  – Indicate that reduced aldosterone will cause salt wasting, and, in females, increased androgen secretion will cause virilization.

• Shortcut:
• Notice that androgens are increased when the deficient enzyme ends in 1 (both 11 beta-hydroxylase and 21 alpha-hydroxylase deficiencies lead to virilization).
• When the deficient enzyme starts with 1, hypertension can occur (both 11 beta-hydroxylase and 17 alpha-hydroxylase deficiencies are associated with increased blood pressure).

Key Drugs:

• Ketoconazole, which is an antifungal drug, blocks steroid hormone synthesis by inhibiting cholesterol side chain cleavage.

• Metyrapone blocks cortisol production via inhibition of 11 beta-hydroxylase; thus, it is used to treat hypercortisolemia.

• Anastrozole and letrozole inhibit aromatase, thereby inhibiting estrone and estradiol production; these drugs can be used as part of anti-breast cancer treatments.

• Finasteride blocks 5 alpha-rectuase, and, therefore, conversion of testosterone to dihydrotestosterone; finasteride, aka, propecia, is used to treat enlarged prostate and male hair loss.