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.

Overview:

• The adrenal gland is structurally and functionally divided into the outer cortex and inner medulla.
• Cortex
  – Embryologically derived from mesoderm
  – Produces steroid hormones from cholesterol.
  – The cortex can synthesize cholesterol de novo, but about 80% of the cholesterol used is obtained from circulating LDLs.
  – Each of the three layers of the adrenal cortex is regulated by ACTH (adrenocorticotropin), though the outermost layer, the zona glomerulosa, is primarily regulated by angiotensin II.
  ACTH upregulates adrenocortical cell LDL receptors and increases enzymatic activity of cholesterol side chain cleavage, which releases cholesterol from the LDLs.
  – Steroid hormones are metabolized in the liver, and secreted in the feces and urine.
• Medulla
  – Neural crest cell origins.
  – Secretes catecholamines in response to sympathetic nervous system stimuli (the adrenal medulla is sometimes called a specialized ganglion).

Anatomy – Blood Supply

• The adrenal gland receives substantial blood flow given its relatively small size.
• The right and left adrenal glands are situated at the superior poles of the kidneys (thus, their alternative name, “suprarenal glands”).
• We show the aorta and renal arteries, and the vena cava and the left renal vein.
• The inferior phrenic arteries arise from the aorta and give rise to the superior suprarenal arteries, which supply the superior regions of the adrenal glands.
• The middle suprarenal arteries arise directly from the aorta and travel to the adrenal glands.
• The inferior suprarenal arteries branch off the renal arteries.
• Venous drainage of the adrenal glands is asymmetrical:
  – The right adrenal gland drains directly into the vena cava, but, because of its relative distance from the vena cava, the left adrenal gland first drains into the left renal vein.

Physiology – Hormone secretion

Cortical hormones

• These are the steroid hormones, which are regulated by ACTH.
• Neurosecretory cells originate in the arcuate nucleus of the hypothalamus, and their axons terminate on capillaries of the hypothalamic-pituitary portal system.
• The hypothalamus secretes Corticotropin-Releasing Hormone (CRH) into the neurosecretory cells.
• When it reaches the anterior pituitary, CRH stimulates corticotrophin release of ACTH, which then travels in the blood to the adrenal cortex.
• In response to ACTH, the adrenal cortex releases cortisol and androgens.
• Regulation of Hypothalamic-Pituitary Axis:
  – At the hypothalamus: Hypoglycemia and stress trigger the release of CRH, whereas ACTH and Cortisol provide negative feedback.
  – ACTH negative feedback on the hypothalamus represents a “short feedback” loop, whereas the cortisol negative feedback is a “long feedback” loop.
  – At the anterior pituitary gland: Cortisol provides negative feedback to inhibit the release of ACTH.
  – This is the “short feedback” loop for cortisol.
• Aldosterone: ACTH also stimulates aldosterone secretion – however, aldosterone secretion is primarily regulated by the renin-angiotensin II response to low renal blood pressure, and, by extracellular potassium concentrations.
  – Thus, low renal blood pressure and elevated potassium levels stimulate aldosterone secretion.

Medulla hormones

• The adrenal medulla is regulated by the sympathetic nervous system: preganglionic sympathetic fibers release acetylcholine on the chromaffin cells of the medulla, which triggers catecholamine release.

Histology and Hormones

• From outer to inner, show the capsule, cortex, and medulla.
• The cortex comprises three sub-layers, each with their own products:
• The zona glomerulosa produces mineralocorticoids
  – Aldosterone, which regulates salt and water balance – thus, when you think of the zona glomerulosa layer, think: mineralo = Salt.
• The zona fasciculata produces glucocorticoids
  – Cortisol, regulates blood sugar – thus, when you think of the zona fasciculata, think: gluco = Sugar.
  – This layer also produces a small quantity of androgens.
• The zona reticularis produces androgens
  – Specifically, DHEA (dehydroepiandrosterone) and A4 (androstenedione), which regulate sex characteristics – thus, when you think of the zona reticularis, think: androgens = Sex.
  – For completeness, indicate that this layer also produces a small quantity of glucocorticoids.
• The *medulla, which comprises the center of the adrenal gland, produces norepinephrine and epinephrine – so, think medulla = Sympathetic nervous system.

Notice that we’ve indicated, from superficial to deep: Salt, Sugar, Sex, and Sympathetic regulation (hence, the mnemonic “the deeper the sweeter” doesn’t capture the full range of adrenal functions, it only describes the cortex!).

• Capsule comprises fibrocollagen fibers and capillaries.
• Zona glomerulosa comprises secretory cells with round nuclei arranged in irregular, rounded nests or clusters – aka, glomeruli.
  – Indicate that these nests are separated by fibrous extensions of the capsule – these are the trabeculae.
  – This is the thinnest layer of the cortex.
• Zona fasciculata comprises columns or cords – aka, fascicles– of cells separated by collagen fibers and capillaries.
  – These cells have abundant cytoplasm, which stains pale due to the presence of abundant lipid droplets.
  – This is the widest layer of the cortex.
• Zona reticularis comprises small branching cells that form a network – aka, reticulum – with capillaries.
  – Because these cells have low lipid levels, they stain dark; indicate that you may see brown lipofuscin pigments in this layer.
• Medulla comprises chromaffin, which are arranged in clusters around venous channels that deliver catecholamines to the blood.

HORMONE SYNTHESIS, TRANSPORT, BINDING, AND EFFECTS.

Three classes of hormones:

• Peptides and proteins (P&P)
• Steroids (S)
• Amines (A)
  – Catecholamines (C)
  – Thyroid hormones (T)

4 hormone physiology features:

Synthesis

• Hormones can be made in advance and stored prior to secretion.
  – The peptide and protein hormones, and amines follow this model.
• Alternatively, they can be synthesized and secreted on demand.
  – The steroids follow this model.

Transport

• This generally depends on chemical structure.
• Hormones can either:
  – Dissolve and travel freely in the blood – the peptides and proteins and also the catecholamines: they are water soluble (aka, hydrophilic)
  – Bind carrier proteins – the steroid and thyroid hormones are less water soluble and travel bound to carrier proteins.

Receptor binding

• The chemical relationship between hormones and target cell membranes determines whether hormones:
  – Bind surface membrane receptors – the peptide and protein hormones and the catecholamines, and in some cases, steroid hormones where they have non-genomic effects on the cell.
  – Bind intracellular receptors — because they are lipophilic (lipid soluble), steroid hormones and thyroid hormones readily slip past the cell membrane to bind with cytoplasmic and/or nuclear receptors.

Mechanism of Action

• Hormones can modify existing proteins within a cell – the peptide and protein hormones and the catecholamines.
• Or they can trigger protein synthesis – the peptide and protein hormones do this, as well, as do the steroid and thyroid hormones.

Comments on the Amines

• The peptides and proteins almost NEVER behave like the steroids.
• The amines divide into the catecholamines and thyroid hormones:
  – Catecholamines act most like the peptides and proteins.
  – The thyroid hormones act most like the steroids.

Peptide and protein hormones

Synthesis:

• Synthesized and then stored in secretory vesicles.
• First, within the nucleus of a cell, the gene for a hormone is transcribed as mRNA
• The mRNA moves to the ribosomes, where it is translated to create a preprohormone;
• The preprohormone moves to the endoplasmic reticulum, where it is converted to a prohormone;
• Finally, the prohormone is transported to the golgi apparatus to be packaged into secretory vesicles; within these vesicles, peptide cleavage produces the final hormone product.
• The hormone is stored until its release is triggered.

Transport:

• Travels freely in the blood; recall that this is because it is water soluble, and readily dissolves.

Mechanisms of Action:

• Peptide hormone binds cell membrane surface receptor and the hormone-receptor complex activates second messenger systems to initiate protein modification and synthesis.

Steroid hormones

Synthesis:

• Steroid hormones are synthesized in the endoplasmic reticulum and secreted on demand; they are not stored in the cell.
• Cholesterol is the parent of steroid hormones.
  • In the adrenal cortex, Mineralocorticoids, Glucocorticoids, or Androgens are produced.
  • In the testes and ovaries, aka, the gonads, testosterone and estrogen are produced.
  • DHEA (Dehydroepiandrosterone) and Progesterone are important intermediate steroids.

Transport:

• Steroid hormones travel in the blood bound to carrier proteins. Only a small portion of steroid hormones travel freely, or unbound.

Mechanisms:

• When steroid hormones bind intracellular receptors, they activate or repress transcription
• Testosterone can pass through the cell membrane to bind with these intracellular receptors.
• When steroid hormones bind surface membrane receptors, they initiate non-genomic effects via second messenger systems are activated.

DNA STRUCTURE

1. Primary structure: sequence of nucleotides

• Pyrimidines: cytosine and thymine
• Purines: guanine and adenine
• Lends DNA polarity

2. Secondary structure: double helix stabilized by H-bonds

• 10 base pairs per full (360 degree turn)
• Adenine and thymine form TWO hydrogen bonds
• Guanine and cytosine form THREE hydrogen bonds
• 10 base pairs per full (360 degree) helical turn

3. Tertiary structure: relaxed or supercoiled

LEVELS OF COMPACTION

1. Nucleosome: comprises histone octamer and the DNA wrapped around it (1.75 supercoil)
2. Chromatin: DNA and associated proteins

• heterochromatin: highly condensed, not transcribed
• euchromatin: NOT highly condensed, regularly transcribed

3. Solenoid: nucleofilament

HISTONES

• Small basic proteins rich in arginine and lysine
• 5 classes of histones
• Can be acetylated or methylated: regulates local DNA compaction
• H1: binds spacer DNA (20-80 bp) and promotes tight packing of nucleosomes

CLINICAL CORRELATION

Anticancer drugs (chemotherapies)

• Many bind to groove in DNA double helix to prevent DNA replication and transcription in cancerous cells

NUCLEOSIDES

• Comprise a sugar and a base

NUCLEOTIDES

• Phosphorylated nucleosides (at least one phosphorus group)
• Link in chains to form polymers called nucleic acids (i.e. DNA and RNA)

N-BETA-GLYCOSIDIC BOND

• Links nitrogenous base to sugar in nucleotides and nucleosides
• Purines: C1 of sugar bonds with N9 of base
• Pyrimidines: C1 of sugar bonds with N1 of base

PHOSPHOESTER BOND

• Links C3 or C5 hydroxyl group of sugar to phosphate

NITROGENOUS BASES

• Adenine
• Guanine
• Cytosine
• Thymine (DNA)
• Uracil (RNA)

NUCLEOSIDES

• =sugar + base
• Adenosine
• Guanosine
• Cytidine
• Thymidine
• Uridine

NUCLEOTIDE MONOPHOSPHATES – ADD SUFFIX ‘SYLATE’

• = nucleoside + 1 phosphate group
• Adenylate
• Guanylate
• Cytidylate
• Thymidylate
• Uridylate

Add prefix ‘deoxy’ when the ribose is a deoxyribose: lacks a hydroxyl group at C2.

• Thymine only exists in DNA (deoxy prefix unnecessary for this reason)
• Uracil only exists in RNA

NUCLEIC ACIDS (DNA AND RNA)

• Phosphodiester bonds: a phosphate group attached to C5 of one sugar bonds with
  -OH group on C3 of next sugar
• Nucleotide monomers of nucleic acids exist as triphosphates
• Nucleotide polymers (i.e. nucleic acids) are monophosphates
• 5′ end is free phosphate group attached to C5
• 3′ end is free -OH group attached to C3

• Mean arterial pressure is determined by cardiac output and total peripheral resistance (aka, systemic vascular pressure).
  – Thus, hypertension, which is elevated blood pressure, is the result of increased cardiac output and/or increased total peripheral resistance.
  – Cardiac output is the product of heart rate and stroke volume.
  – Stroke volume is determined by preload and contractility.
  – Blood volume contributes to preload, by way of increased venous return.
  – The degree of sodium and water retention in the kidneyscontributes to blood volume.
  – Degree of vasoconstriction, particularly of the small arteries and arterioles, is a significant determinant of total peripheral resistance.

Key mediators of blood pressure implicated in primary and/or secondary hypertension
– Notice that many of these mediators effect both cardiac output and total peripheral resistance, but be aware that some effects may be more significant in hypertension development than others.

• Posterior pituitary secretes antidiuretic hormone (aka, vasopressin),
  – Vasoconstrictor that also increases sodium and water retention in the kidneys.
  – Increased sodium and water retention results in increased blood volume, and, therefore, increased cardiac output.
• Aldosterone is secreted by the adrenal cortex and has similar effects.
• Angiotensin II, which is a product of the renin-angiotensin-aldosterone system, has direct and indirect effects on blood pressure:
  – Like antidiuretic hormone and aldosterone, it triggers vasoconstriction and increases sodium and water retention.
  – Angiotensin II also stimulates the release of norepinephrine, antidiuretic hormone, and aldosterone, further enhancing vasoconstriction and sodium/water retention.
  – Multiple antihypertensive drugs work against the effects angiotensin II.
• Norepinephrine is a vasoconstrictor that also increases heart rate and contractility.
• Vascular remodeling: hypertension produces damage and inflammation that leads to vascular remodeling, which alters local mediators.
  – Endothelin, which is a key vasoconstrictor, is elevated in remodeled vessels.
  – Secretion of local vasodilators, such as nitric oxide, is reduced.
• Vasodiators: nitric oxide, prostaglandins, histamine, and bradykinin.
  – Bradykinin is broken down by angiotensin II; thus, angiotensin II not only induces vasoconstriction, it removes a vasodilator.
  The relationship between angiotensin II and bradykinin contributes to the effectiveness of drugs that inhibit angiotensin-converting-enzyme – when circulating levels of angiotensin II are reduced, bradykinin levels can rise.

• Genetic and epigenetic factors, diet, physical activity levels, and other environmental or biological factors can affect blood pressure by acting on the various components of this diagram.
  – For example, we can now understand how individuals who are salt-sensitive or have aldosterone-secreting tumors develop hypertension via elevated blood volume and preload.

• Hypertensive crisis occurs when blood pressure is dangerously high, typically exceeding 180/120mmHg.
  – Hypertensive urgency: no end-organ damage
  – Hypertensive emergency: end-organ damage has occurred
• Symptoms of hypertensive emergency include severe headache with confusion and impaired vision, chest pain and shortness of breath, nausea/vomiting, anxiety, and seizures.

• Hypertension is characterized by sustained elevated blood pressure.
• Hypertension is common worldwide, and, according to updated guidelines, approximately 46% of Americans 20 years and older have hypertension.
  – Many of these individuals are unaware of their status, which is why hypertension is sometimes referred to as a “silent killer.”
• Hypertension predisposes patients to cardiovascular disease,which is one of the most common causes of death in both men and women worldwide.

• Systolic pressure is the highest arterial pressure, reached after blood is ejected from the left ventricle.
  – 120 mmHg
• Diastolic blood pressure is the lowest arterial pressure, reached during ventricular relaxation.
  • 80 mmHg
• Mean arterial pressure is determined by Cardiac Output and Total Peripheral Resistance.
  • 93 mmHg
• Cardiac output refers to the amount of blood ejected by the left ventricle in in one minute
• Total Peripheral Resistance refers to the resistance of the systemic arteries to blood flow (total peripheral resistance is also referred to as systemic vascular resistance, SVR).
• Hypertension occurs when the cardiac output and/or total peripheral resistance increases.

Classification of Hypertension: 2017 guidelines by the American College of Cardiologists and American Heart Association.

• Healthy/normotensive: Systolic blood pressure less than 120 mmHg, and diastolic pressure less than 80 mmHg.
• Elevated: Systolic blood pressures between 120 and 129 mmHg, and diastolic pressures less than 80 mmHg.
• Stage 1 hypertension: Systolic pressures between 130 and 139 mmHg, OR diastolic pressures between 80 and 89 mmHg.
• Stage 2 hypertension: Systolic pressures above 140 mmHg, OR diastolic pressures above 90 mmHg.
• The higher value determines the stage of hypertension if the systolic and diastolic values fall in different categories.
  • For example, if a patient’s systolic pressure is 135 mmHg and but diastolic pressure is 75 mmHg, it would be classified as Stage 1 hypertension.

• Blood pressure fluctuates throughout the day and in response to various situations, so multiple measurements need to be taken in and out of the health clinic, and during waking and sleeping.
  One frustrating aspect of measuring blood pressure is that the presence of a health care professional can affect the blood pressure! This may be due to sympathetic activation in response to anxiety or other factors.
• “White coat hypertension” occurs when an untreated patient has high blood pressure in the presence of a medical professional, but is otherwise normotensive.
  • “White coat effect” is the same phenomenon, but in patients who are under treatment for high blood pressure.
• “Masked hypertension” is when an untreated patient is normotensive in the presence of a medical professional but is hypertensive otherwise;
  • “Masked uncontrolled hypertension” is the same phenomenon, except in patients who are being treated for hypertension.

Primary Hypertension

• Accounts for 90-95% of all adult cases.
• In primary hypertension, there is no single identifiable cause. Instead, one or more of the following factors contribute to high blood pressure.
  • Some variables are modifiable, and many are interrelated.
• Genetic and epigenetic factors can contribute to development of high blood pressure.
• Obesity contributes to hypertension via various direct and indirect mechanisms; for example, some propose that dysfunction in the sympathetic nervous system and kidneys contribute to high blood pressure in obese patients.
• Sedentary lifestyles which are common in societies where we spend several hours per day at our desks. — — — Increasing physical activity confers multiple protective effects on the cardiovascular system.
• Diet is a significant predictor of hypertension
  • Particularly salt intake and salt sensitivity.
    Salt sensitivity refers to how efficiently individuals excrete salt and, therefore, avoid
    elevations in blood pressure. Exactly what determines salt sensitivity is uncertain, but African-Americans, the elderly, and post-menopausal women seem to be particularly susceptible to elevations in blood pressure due to lower rates of salt excretion.
• On the other hand, inadequate intake of other nutrients,including calcium, potassium, vegetable proteins, and fiber may also contribute to hypertension.
• Alcohol as well as electronic and tobacco cigarettes are associated with hypertension due to their effects on the sympathetic nervous system and other regulators of blood pressure.
• Chronic stress, including psychosocial stress, also contributes to hypertension; this may be due to activation of the sympathetic nervous system and/or other physiological reactions to stress.
• Population differences
  • Hypertension prevalence varies by population, and are likely due to differences in both genetic and environmental factors.
  • There are dramatic differences in the prevalence of hypertension in United States subpopulations, due to both genetic and environmental differences.
  • Hypertension prevalence is highest in non-Hispanic African Americans, American Indians, and Native Alaskans as compared to non-Hispanic Caucasian Americans and Hispanic Americans.
  • Hypertension prevalence also varies by age and sex:
    In general, hypertension prevalence increases with age.
    Premenopausal women typically have lower blood pressures than do age-matched men or post-menopausal women.
    However, post-menopausal women have blood pressures equal to or higher than their age-matched male peers.

Secondary Hypertension

• Accounts for 5-10%* of adult hypertension.
• In secondary hypertension, an underlying condition causes the elevation in blood pressure.
• Renovascular hypertension occurs when renal artery stenosis prevents blood from reaching the kidneys; in response to low oxygen levels, the kidneys release hormones that increase blood pressure.
  • Notice that the adaptive physiological response to low oxygen levels is, in this case, contributing to pathology.
  • Two key causes of renal artery stenosis and renovascular hypertension are atherosclerosis and fibromuscular dysplasia.
• Obstructive sleep apnea
• Primary aldosteronism is characterized by adrenal glands that release excess aldosterone, which leads to increased sodium and fluid retention, and, therefore, increased blood volume and pressure.
  • Two key causes of primary aldosteronism and hypertension are aldosterone-producing adenomas and bilateral idiopathic hyperaldosteronism.
• Renal parenchymal diseases also lead to hypertension due to inadequate blood volume regulation by damaged renal tissue.
• Drugs
  • Examples: caffeine, NSAIDS, hormonal contraceptives (especially those with synthetic estrogen), decongestants, cocaine, amphetamines, and some herbal agents.
• Pregnancy:pregnant women can develop gestational hypertension, which can lead to pre-eclampsia (aka, toxemia).
  • Hypertension is a significant cause of morbidity and mortality in both mothers and their neonates, and women who are hypertensive prior to pregnancy require special attention.

Additional Causes of Secondary Hypertension

• Pheochromocytoma
• Coarctation of aorta (children)
• Cushing syndrome
• Hyperparathyroidism

Typical genotype-phenotype relationships:

46 XX, female-typical phenotype

• Primordial germ cells in the gonadal ridge induce ovarian differentiation, in approximately week 8.
• Genes from the Wnt family and others transform the paramesonephric ducts to produce the uterine tubes, uterus, and the vagina.
• Estrogen from the fetal ovaries and placenta guide formation of the vulva, aka, the female external genitalia.

46 XY, male-typical phenotype

• The SRY gene in the somatic cells of the gonadal ridge induces testes differentiation.
• Subsequently, the testes produce androgens and anti-Mullerian hormone (AMH), which facilitate transformation of the mesonephric ducts to produce the tubules of the testes, the epididymis, and the ductus deferens.
• Androgens also guide formation of the male external genitalia, the penis and scrotum.

DSDs caused by atypical sex chromosome number:

DSD 45 X_, aka, Turner Syndrome

• The genotype tells us that there are 45 total chromosomes, with one X chromosome; thus, one of the sex chromosomes is missing.
• Gonads do not fully differentiate, and typically present as fibrous, non-functional streak ovaries.
  • As a result, most 45 X_ individuals do not pass through puberty, and typically have impaired fertility.
  • Other notable characteristics include short stature, which becomes noticeable during childhood; broad chest; and a “webbed” neck, with extra skin folds. Be aware that these features are not present in every individual, but, when present, may be indicative of an atypical genotype.
  • Clinical concerns include cardiac and renal defect, and lymphedema.

DSD 47 XXY, aka, Klinefelter’s syndrome.

• Extra X chromosome in each cell.
• The extra X chromosome impairs testes development, resulting in small testicles that produce less testosterone.
• Thus, puberty is often delayed or incomplete, and fertility is impaired.
• Individuals tend to experience gynecomastia (enlargement of the breast tissue); reduced body and facial hair; and, perhaps most obviously, tall stature with long extremities.
• Clinical concerns are increased breast cancer risk (relative to typical male rates) and, in some cases, learning disabilities.

DSD 45 X, 46 XY, aka, mixed gonadal dysgenesis

• A type of mosaicism; in these individuals, some cells have the 45 X genotype, others have the 46 XY genotype.
• Streak ovaries and testis, which is likely to be undescended; puberty is likely to be incomplete, and fertility is impaired.
• Clinical implications are short stature and cardiac and renal defects (similar to Turner Syndrome).

DSD 46 XX, 46 XY, aka, chromosomal ovotesticular DSD

• Mosaic
• Both testicular and ovarian tissues are present, either symmetrically or asymmetrically.
• The resulting phenotype depends on the functionality of the gonadal tissues and the hormones they produce.
• Clinical concerns include hypospadias (displaced urethral opening) and cryptorchidism (undescended testes), both of which are likely the result of deficient androgen influence.