Endocrine and Reproductive Physiology

7/28/2019 Endocrine and Reproductive Physiology

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ENDOCRINE/REPRODUCTIVE

PHYSIOLOGY

PHY 546

Jill Davis

Cleveland Chiropractic CollegeKansas City


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Chemical Messaging

Exocrine

Ducted glands

Secretes substances into hollow organs or body surface Endocrine

Ductless glands

Secrete hormones into bloodstream

Paracrine

Cells secrete substances that affect neighboring cells


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Chemical Messaging

Autocrine

Secretes substances that affect the cell which

secreted the substance Neural signaling

Neurotransmitters secreted by neurons

Paracrine/autocrine signaling

Neuroendocrine signaling

Hormone secreted into blood by a neuron


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Endocrinology Basics

Anatomy/histology of each gland

Hormone(s) secreted

Chemical classification

Synthesis

Target tissue(s)

Receptor type and mechanism


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Endocrinology Basics

Major effects of the hormone

Regulation of secretion

What stimulates secretionWhat inhibits secretion

Common pathologies concerning

hypersecretion Common pathologies concerning

hyposecretion


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Hormone classification

Peptides/proteins

Amine Hormones (derived from tyrosine)

Catacholamines

Thyroid hormones

Steroids


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Peptide/protein Hormones

Structurepeptide (100 a.a.)

Solubilityhydrophilic

Synthesison RER, packaged in Golgi

Storagemostly in secretory granules

Secretionexocytosis of granules

Plasma transportas free hormone Receptor sitecell membrane


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Catacholamines

Structuretyrosine derivative

Solubilityhydrophilic

Synthesisin cytosol

Storagein chromaffin granules

Secretionexocytosis of granules

Plasma transportsome free/ some bound toplasma proteins

Receptor sitecell membrane


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Thyroid Hormones

Structureiodinated tyrosine

Solubilitylipophilic

Synthesiscolloid space of thyroid gland

Storagein colloid and cytosol in thyroid cells

Secretionendocytosis from colloid/diffusion

Transportbound to plasma proteins Receptor sitenucleus of target cell


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Steroids

Structurecholesterol derivative

Solubilitylipophilic

Synthesisvarious intracellular compartments

Storagenone

Secretiondiffusion

Plasma transportbound to plasma proteins Receptor sitecytosol or nucleus


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Overview of Endocrine Glands

Hypothalamusvarious releasing and inhibitoryhormones (most are peptides)

Anterior PituitaryTSH, ACTH, Prolactin, FSH,LH (peptides)

Posterior PituitaryADH/vasopressin, oxytocin(peptides)

Thyroidthyroxine and triiodothyronine (amines) Adrenal Cortexcortisol, aldosterone (steroids)

Adrenal medullanorepinephrine/epinephrine(amines)

Pancreasinsulin, glucagon (peptides)


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Overview of Endocrine Glands

Parathyroidparathyroid hormone (peptide)

Testestestosterone (steroid)

Ovariesestrogens, progesterone (steroids) PlacentaHCG (peptide), others

KidneyRenin, EPO (peptides), 1,25Dihydroxycholecalciferol (steroid)

Heartatrial natriuretic peptide

Stomachgastrin (peptide)

Small intestine - secretin, CCK (peptides)


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Regulatory Mechanisms

Negative feedback

Positive feedback (rarely)

Cyclical patterns of secretion


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Transport

Water soluble hormones (peptides &

catacholamines)dissolved in plasma

Lipid soluble hormones (steroids & thyroid

hormones)bound to plasma proteins


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Clearance

Hormone concentration in blood

Rate of secretion

Clearance rate

Metabolic destruction

Biding to tissues

Excretion by liver into bile Excretion by kidneys into urine

Bound vs. unbound hormones


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Terminology

Down regulation

a hormone induced response that produces

fewer hormone receptors on the target cellDesensitizationfunctional response in target

tissue to hormone down regulation


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Terminology

Up regulation

a hormone induced response that produces morehormone receptors on the target cell.

Sensitizationthe functional response in target tissuesto hormone up regulation

Antagonism

two hormones having opposite effects on the targettissue

or causes down regulation of another hormonesreceptor.


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Terminology

Permissiveness

Where one hormone must be present in order

for another to be effective

Synergism

Where two hormones produce complementaryeffects when combined (two hormones up-

regulate each other)


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Hormone Receptor Locations

In/on cell surface

Integral to or attached to the cells membrane

Used by peptide/protein and catacholaminehormones

In the cell cytoplasm

Used by steroid hormones

In the cell nucleus

Used by thyroid hormones


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Basic Actions of Hormone-

receptor Binding Change in membrane permeability

Activation of extracellular receptor

Opening or closing of ion channels

Action can be direct (first messenger) or

indirect (activation of second messenger)


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Basic Actions of Hormone-

receptor Binding Activation of intracellular enzyme

Activation of extracellular receptor

Activation of intracellular second messenger

Activation of genes

Activation of intracellular receptor

Leads to activation of DNA within nucleus, orincreased mRNA translation


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Review of Second Messenger

Systems Second messengersan intracellular chemical

messenger that is activated by the binding of anextracellular chemical messenger (first messenger)to a surface receptor.

G-protein (GTP binding protein)mediatesactivation of second messenger enzyme. Thereare several forms of this protein.

Amplificationsuccessive steps of activationcause multiple second messengers to be formedfrom binding of one first messenger

Adenylyl CyclasecAMP system (fig 74-4)


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Review of Second Messenger

Systems Phospholipase CPIP2IP3 + DAG

system (fig 74-5)

Calcium-Calmodulin system


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Pituitary Gland (Hypophysis)

Locationsella turcicaattached to

hypothalamus via pituitary stalk

Anatomy

Anterior lobe (adenohypophysis, pars distalis)

Intermediate lobe (pars intermedia)

Posterior lobe (neurohypophysis, pars nervosa)


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Anterior Lobe

Histology

Derived from Rathkes pouch

Acidophilic cells SomatotrophsGH

Lactotrophsprolactin

Basophilic cells

CorticotrophsACTH ThyrotrophsTSH

GonadotrophsFSH, LH


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Posterior Lobe

Histology

Pituicytesneuroglial-like cells

Axons of neuroendocrine cells Expanded axon terminals = Herring bodies

Cell bodies are located in supraoptic and

paraventricular nuclei of hypothalamus.

Connected via hypothalamo-hypophyseal tract


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Intermediate Lobe

Histology

Also derived from Rathkes pouch

Is a rudimentary structure in humans

Produces some hormones

Melanocyte stimulating hormone (MSH)

Opiates (POMC, endorphins)


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Hypothalamic Control of

Pituitary Secretions Anterior Pituitary

Neurosecretory cells of the hypothalamus secrete

releasing and inhibiting hormones:

Thyrotropin-releasing hormone (TRH)

Corticotropin-releasing hormone (CRH)

Growth hormone releasing hormone (GHRH)

Growth hormone inhibiting hormone (GHIH)

Gonadotropin-releasing hormone (GnRH)

Prolactin inhibitory hormone (PIH)

Hypothalamic-hypophyseal portal system


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Hypothalamic Control of

Pituitary Secretions Posterior Pituitary

Nerve signals from the hypothalamus terminate

in the posterior pituitary gland and controlsecretion.

Supraoptic nucleusADH (vasopressin) primarily

Paraventricular nucleusoxytocin primarily


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Pituitary Hormones Adenohypophysis

Human growth hormone (hGH, somatotropin)

Adrenocorticotropin (ACTH)

Thyroid-stimulating hormone (TSH)

Gonadotropic hormones

Follicle stimulating hormone (FSH)

Luteinizing hormone / (LH)

Prolactin / (PRL)

Neurohypophysisstores and secretes only Antidiuretic Hormone (ADH, vasopressin)

Oxytocin


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Growth Hormone

A.k.a.somatotropic hormone or

somatotropin

ClassificationProtein

SynthesisGH mRNA codes a

prehormone, which is cleaved to form GH,

stored in secretory vesicles


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Growth Hormone

Target Tissues

Almost all tissues of the body capable of

growingSome tissues affected differently than others

Secreted in pulses


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Growth Hormone

Growth effects

increase cell size and/or stimulates mitosis

Stimulates differentiation of bone and muscle cells Metabolic effects - Protein

Increased rate of protein synthesis in most tissues

Increased amino acid transport into cells

Increased mRNA translation Increased mRNA transcription

Decreased catabolism of protein


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Growth Hormone

Metabolic Effects - Fats

Increased mobilization of fatty acids from

adipose tissue Release of fatty acids increase blood concentration

May lead to ketosis if excessive

Increased utilization of fatty acids for energy

Enhances conversion of fatty acids to acetyl Co-A


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Growth Hormone

Metabolic EffectsCarbohydratesDecreased glucose uptake in skeletal muscle

and fat

Increased glucose production in liver

Increased insulin secretion (may becompensatory)

Carbohydrate effects may be due to release of

fatsSynergismGH and insulin are both necessary

for growth


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Growth Hormone

Somatomedin (Insulin-like GF)

GH stimulates its release from liver

Mediates GHs effect on bone growth


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Growth Hormone

Regulation of GH secretion

Stimulates secretion:

Starvation / protein deficiency Hypoglycemia or low FA in blood

Exercise

Excitement

Trauma

First 2 hours of deep sleep


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Growth hormone

Hormonal Regulation

Growth hormone releasing hormone

Secreted from the hypothalamus (ventromedial nucleus)

Stimulates somatotrophs via cAMP pathway

Has both long term and short term effects

GH - negative feedback loop

Growth hormone inhibitory hormone (somatostatin)

Secreted from the hypothalamus

May be stimulated by GH

Probably less important regulator of GH secretion


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Growth Hormone Clinical Correlations

Panhypopituitarism Decreased secretion of all all adenohypophyseal hormones

Congenital or caused by pituitary destroying tumor, orthrombosis of pituitary gland

Effectshypothyroidism, adrenal insufficiency, infertility,

dwarfism (in children) Dwarfism

Panhypopituitarism or GH deficiency alone

Can be mutation in gene for somatomedin

Giantism(children, teens)

Growth hormone secreting tumors of pituitary gland

Tall stature, hyperglycemia,

Acromegaly (adult)

Enlargement of especially membranous bones


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Antidiuretic Hormone (ADH)

A.k.a.vasopressin

Structurepolypeptide

Produced by neurosecretory cells of the

supraoptic nucleus (~66%) and released by

posterior pituitary by exocytosis

Target tissueskidney and arterioles


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Antidiuretic Hormone (ADH)

Effects on collecting ducts / tubules of the nephron(kidney)

MechanismcAMP phosphorylation of aquaporin-containing vesicles inserts into tubular membraneincreases H2O permeability increases H2O

reabsorption Effectantidiuresis

Reversible

Effects on arterioles

Causes vasoconstriction increases blood pressure

Effect seen in higher concentrations


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ADH

Regulation of ADH secretion

Osmotic regulation

osmoreceptors in hypothalamus sense increased

electrolyte concentration increase ADH secretion

Decreased blood volume and arterial pressure

stretch receptors in atriaoverfilling inhibits ADH

secretion

Baroreceptors in carotid, aortic, pulmonary arteries

too much pressure inhibits ADH


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Oxytocin

Structurepolypeptide

Produced by neurosecretory cells of the

paraventricular nucleus (~66%) andreleased by posterior pituitary by exocytosis

Target Tissuesuterus and breast


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Oxytocin

Effect on uterus

Stimulates smooth muscle contraction

important for delivery of babies Effect on breast

Stimulates myoepithelial cells in mammary

alveoli to contract to cause milk let down intothe ducts

Stimulated by suckling


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Thyroid Gland

Location - near junction of larynx and trachea

Anatomy - Right and left lobes connected by

isthmus Histology

Folliclessimple cuboidal epithelium lining a colloid-

filled lumen (thyroglobulin)

Parafollicular cells (clear cells)

Has an extensive blood supply


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Thyroid Hormones

Synthesis Iodide

Absorbed from the GI tract

Iodide trappingactive transport of I- into follicle cells

Transported to lumen of follicle and oxidized by peroxidase /

H2O2 to form iodine

Thyroglobulin Synthesized by RER and Golgi

Is a large glycoprotein containing many tyrosine residues

Iodinase links iodine to tyrosine residues to create MIT, andDIT

2 DIT are linked together to form thyroxine (T4)

1 MIT and 1 DIT are linked to form triiodothyronine (T3)


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Thyroid Hormones

Thyroglobulin is the storage form of T3 andT4 in the thyroid gland

Release of T3 and T4Pseudopod extension and pinocytosis

Lysosomal proteinase cleavage of T3, T4, MIT,and DIT off of thyroglobulin

MIT and DIT are deiodinated and recycled

T3 and T4 are released into the blood


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Thyroid Hormones

Secretion rates

93% thyroxine (T4)

7% triiodothyronine (T3)T3 is most potent, however, T4 slowly becomes

deiodinated in the blood to form T3

Transport

Strongly bound to plasma proteins

Slow release to tissue cells


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Thyroid Hormones - Functions

Nuclear receptors

Hormone-receptor complex functions as a

transcription factor 100s of genes are activated therefore 100s of

proteins are synthesized

All responses to thyroid hormones are

secondary to this increase


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Thyroid Hormones - Functions

Increases basal metabolic rate (kcal/m2/hr)

Increases rate of utilization of foods for energy

Increases protein synthesis AND catabolism

Increases # and size of mitochondria

Increases ion transport

Decreases body weight/increases appetite


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Thyroid Hormone - Functions

Carbohydrate metabolism Increases uptake

Increases glycolysis

Increases gluconeogenesis

Increases absorption

Increases insulin secretion

Fat metabolism

Increases mobilization and utilization of free fatty acids

Decreases cholesterol, phospholipids and triglycerides(more is secreted in the bile)


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Thyroid HormoneFunctions

Other systemic effects

Increased CO and Q (blood flow)

Due to increased demand / autoregulation Increased heat skin vasodilation

Increased HR and strength of contraction (however

too much can weaken heart)

Increased respiration

Increased GI motility


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Thyroid Hormone - Functions

Other systemic effects - continued

Excitatory to nervous system (reduced sleep)

Muscle irritabilitytremor

Increased endocrine gland secretions

Increased growth rate

Important in fetus and infancy Matures epiphyseal plate


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Regulation of Thyroid Hormone

Secretion TSHthyroid stimulating hormone , thyrotropin

From adenohypophysis

Increases T3 and T4 secretion

protolysis of thyroglobulin iodide pump activity

size of thyroid cells

TSH is in turn controlled by TRH

Thyrotropin releasing hormone

From hypothalamus


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TRH and TSH Regulation

Exposure to coldincreases TRH and

therefore TSH as well

Anxiety and excitementdecreases TRHand TSH

Thyroid hormonesnegatively feedback on

TSH


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Hyperthyroidism

Causes Graves Diseaseautoimmune disease

Thyroid adenomatumor

Symptoms

Hyper-excitability Intolerance to heat / sweating

Weight loss

Muscle weakness

Inability to sleep Tremors (hands)

Exopthalmos


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Hypothyroidism

Causes Thyroiditisautoimmune

Iodide deficiency

others

Symptoms

Opposite to that of hyperthyroidism

Cretinisminfancy/young childhooddecreased

mental development Myxedemaadultaccumulation of fluidpuffyfeatures.


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Adrenal Gland

Locationat the superior poles of each kidney

Anatomy

Capsule surrounded by adipose

Cortex- secretes the corticosteroids

Medullafunctionally related to the SNS

HistologyAdrenal cortex

Zona glomerulosaunderneath capsule Zona faciculatamiddle layer

Zona reticularisdeep layer near medulla


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Adrenal Glands - Hormones

Cortex (corticosteroids)

Mineralcorticoids (aldosterone)

Glucocorticoids (cortisol)Sex steroids (androgens, estrogens)

Medulla

Epinephrine (adrenalin)Norepinephrine (noradrenalin)


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Adrenal Cortex

Mineralcorticoidseffect electrolyte

balance

Aldosterone (most potent, 90% of total activity)Desoxycorticosterone (low secretion, low

activity)

Secreted by zona glomerulosa


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Adrenal Cortex

Glucocorticoidseffect macronutrientmetabolism

Cortisol (most potent, 95% total activity)

Corticosterone (little activity)

Secreted by zona fasciculata

Sex steroids

DHEA and androstenedione

Precursors to testosterone and estrogens

Secreted by the zona reticulata


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Adrenal Cortex

Corticosteroid synthesis

Synthesized from cholesterol

De novo synthesis from acetate (small amounts) LDL in plasma

Cholesterol converted in mitochondria to

pregnenolone

Pregnenolone is transported to SER for further

steps in the pathway (se fig 77-2)


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Adrenal Cortex

Corticosteroid Transport

90-95% cortisol bound to plasma proteins

60% aldosterone bound to plasma proteins

Metabolismoccurs in the liver

Secreted into bile

Excreted by kidneys


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Aldosterone

Target Tissues

Kidney (distal tubules and collecting duct)

Large intestine epitheliumSweat glands

Salivary glands

Effects

Increased reabsorption of sodium coupled withincreased excretion of potassium


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Aldosterone

Mechanism

Lipid soluble

Cytoplasmic receptor proteinDiffusion into nucleus

Induces gene transcription

Increase synthesis of enzymes and membrane

transport proteins Sodium-potassium ATPasebasolateral membranes

Sodium channel proteinluminal membrane


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Aldosterone

Effects on Kidney DT and CD

Increases Na reabsorption

increases K excretionIncreases water absorption

Increases extracellular fluid volume / increases

blood pressure aldosterone escape and pressure natriuresis

and diuresis


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Aldosterone

Effects on Sweat glands and Salivary glands

Increases Na absorption and increases Kexcretion

Conserves Na loss in saliva and sweat

Effects on Intestinal epithelial cells

Increases Na absorption and increases K

excretionPrevents loss of sodium in stools and therefore

water is absorbed


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Aldosterone

Regulation of Aldosterone Secretion

Stimulation of secretion

Hyperkalemia

Renin-angiotensin system

Inhibition of secretion

Hypernatremia (slightly)

Permissive hormone ACTHnecessary for aldosterone secretion, but

does not control rate of secretion


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Hypo-secretion of Aldosterone

Hyperkalemia

Hyponatremia (and decreased Cl)

Decreased extracellular fluid volume

Decreased cardiac output

Arrhythmia (heart failure)

Hypovolemic (circulatory shock)

Death in a few days-weeks

Addisons Disease autoimmune disease, TB,cancer, also effects glucocorticoids


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Hyper-secretion of Aldosterone

Primary aldosteronism / Conns Syndrome

caused by tumor of ZG cells

Kypokalemia [NaCl] near normal because of pressure natriuresis

ECF volume increases (reaches max because of

pressure diuresis)

Hypertension

Muscle weakness


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Cortisol

Principle Target Tissues

Liver

Skeletal muscleAdipose tissue

Mechanism

Similar to aldosterone


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Cortisol Effects Acts permissively to facilitate mobilization of

fuels

Carbohydrate metabolism

Increases gluconeogenesis and glycogenesis (liver)

Increases glucose-6-phosphatase (liver)

Decreases sensitivity to insulin

Decreases glucose uptake

Protein metabolism

Accelerates protein breakdown, inhibits synthesis (mostly in

muscle)

Decreases amino acid uptake

Conversion of protein to glycogen (liver)


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Cortisol Effects

Fat metabolism

Increases lipolysis (adipose)

Excess causes preferential fat deposition in trunk,

face, abdomen


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Cortisol - Effects

Resists stress Sources of stress include: trauma, infection,

temperature extremes, debilitating disease, etc.

Mobilization of fuels from non-essential tissues makesthem available to critical tissues

Anti-inflammatory effects

Decreases arachidonic acid/inflammatory mediators

Stabilizes lysosomes

Decreases leukocyte recruitment Decreases phagocytosis

Decreases T-cell (and indirectly B-cell) activity


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Cortisol - Regulation

CRF (corticotropin-releasing factor)

Hypothalamus

Stimulated by physical or emotional stress,hypoglycemia

ACTH (adrenocorticotropic hormone)

From anterior pituitarySole regulator of cortisol secretion


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Cortisol - Regulation

Cortisol

Negative feedback on CRF and ACTH

secretion Circadian Rhythm

Cortisol secretion is higher in morning than in

evening

C ti l H ti


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Cortisol Hypersecretion

Cushings Syndrome/disease Causes: Adenoma of anterior pituitary ( ACTH) Abnormal CRH release from hypothalamus

Ectopic ACTH secretion from tumor

Adrenal cortex adenoma ( cortisol) Signs & Symptoms

buffalo torso, thin extremities

moon face

Hyperglycemia

Depressed immune function (infections)

Abdominal striae ( collagen) Osteoporosis

May have some symptoms of hyperaldosteronism


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Hypoadrenalism

A.k.a.Addisons disease

Mixedboth aldosterone and cortisol are under-

secreted

Causes - Atrophy of adrenal cortex (autoimmune,

cancer, TB)

Signs & Symptoms

Mineralcorticoid - Na reabsorption, hyperkalemia, reducedECF volume etc.

Glucocorticoidhypoglycemia, muscle weakness, mentalsluggishness, reduced resistance to stress


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Adrenal Medulla

Derived from neural crest

Is analogous to a sympathetic ganglion

Innervated by preganglionic neuron Secretes 80% epinephrine 20%

norepinephrine (catacholamines)

Effects same as for neural release, but lastlonger (released slowly)

Released from chromaffin cells


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Catacholamine Effects

Epinephrine

Adrenergic receptor affinity 1=2, 1 = 2

Reduces peripheral resistance (vasodilation

Heart ratemixed effect

Increased cardiac muscle contractility

Increased lipolysis

Increased metabolism (heat production) Increased glycogenolysis and gluconeogenesis (liver)

Increased glucagon, decreased insulin, increased ACTH


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Catacholamine Effects

Norepinephrine

Also is a neurotransmitter

Adrenergic receptor affinity 1=2, 1>>>2

Increased peripheral resistance (vasoconstriction)

Increased heart rate and contractility

Inhibits lipolysis

Slightly stimulates metabolism Slightly stimulates glycogenolysis and gluconeogenesis


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Adrenal Medulla - Regulation

Stimulation

Sympathetic NS activity

Exercise, stressHypovolemia, hypotension

Inhibition

Parasympathetic activity


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Pancreas

Anatomy

Locationlong tapered organ behind the

stomach and between the duodenum and spleenComposed of head, body, tail

Arises from GI tract as accessory organ

Has both endocrine and exocrine function


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Pancreas

Histology

Exocrinepancreatic acini

secretes digestive juicesEndocrineIslets of Langerhans

cellssecretes glucagon and amylin

cellssecretes insulin

cellssecretes somatostatin

PP cellssecretes pancreatic polypeptide


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Insulin

Structureprotein; 2 polypeptide chainslinked by 2 disulfide bridges

Synthesison ribosomes aspreprohormone, then cleaved toprohormone, then to insulin

Transportunbound

life about 6 minutes in blood

Degraded by insulinase (liver)


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Insulin

Target cells

All cells except brain

Especially effects liver, skeletal muscle,adipose tissue

Insulin receptor linked to tyrosine kinase

which phosphorylates intracellularenzymes, and causes exocytosis of glucose

and amino acid translocator proteins


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Insulin - Effects

Skeletal Muscle Energy source in skeletal muscle At rest with little insulin: fatty acids > glucose

During exercise: glucose > fatty acids

At rest with insulin: glucose > fatty acids

Insulin effects glucose and a.a. transport glycogenesis glycogenolysis glycolysis pyruvate acetyl CoA protein synthesis proteolysis


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Insulin Effects

Liver

glucokinase (glucose trapping)

glycogenesis

glycogenolysis (phosphorylase) gluconeogenesis

glycolysis

pyruvate acetyl CoA (pyruvate dehydrogenase)

lipogenesis (FFA triglycerides LDL)

protein synthesis


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Insulin Effects

Adipose Tissue

glucose transporter

lipoprotein lipasefor transport of fats intoadipose cells (triglyceridesFFA)

Glucose glycerol for triglyceride synthesis

lipogenesis

hormone sensitive lipase


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Insulin Effects

The Big Picture After a meal (especially high carb meals) insulin

secretion increases

Generally, cells will increase uptake and utilization of

glucose rather than fats Cells will store glucose as glycogen until storage is

maximized (liver, muscle)

About 60% of glucose from meal is stored in liver

Excess glucose will be converted to fat (liver, adipose) Brain tissue is always permeable to glucose which is its

primary energy source ; insulin independent


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Insulin Effects

Growth

Both growth hormone and insulin promote

protein formation and prevents degradation ofproteins

Both hormones are necessary for normal

growth (synergism)


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Insulin - Regulation

Stimluates release

Increased blood glucose

Increased blood free fatty acids

Increased blood amino acids (arginine, lysine)

GI hormones (gastrin, cholecystokinin, secretin, gastric

inhibitory peptide)

Glucagon, growth hormone, cortisol Parasympathetic stimulation (Ach)

Insulin resistance (obesity, type II diabetes)


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Insulin Regulation

Inhibits release

Decreased blood glucose

FastingSomatostatin

Catecholamines


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Insulin Deficiency

Diabetes Mellitus

Type 1

Insulin dependent (IDDM) Lack of insulin secretion by pancreas

Autoimmune disease against beta cells (usually)

Type II

Non-insulin dependent (NIDDM)

Decreased sensitivity to insulin (insulin resistance)


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Type 1 Diabetes mellitus Increased blood glucose Glucosurea

Polyurea

Dehydration

Polydipsia Polyphagia with weight loss

Blood vessel damage

Peripheral neuropathy

Hypertension / kidney disease Atherosclerosis

ketoacidosis


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Type II Diabetes Mellitus

More common than type I (80-90%)

Often associated with obesity

Insulin levels increased

Mild hyperglycemia

Beta cell exhaustion

Less problem with ketoacidosis than type I


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Hyperinsulinism

Adenoma of islets of Langerhans (rare)

Insulin shock

Insulin causes excessive drop in plasma glucose Nervous system starves

Initially leads to hallucinations, tremors,

nervousnessAs hypoglycemia progresses, seizures, coma


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Glucagon

Structure: protein

Effects

Increased glycogenolysis (liver)Increased gluconeogenesis (liver)

Activates adipose cell lipase


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Glucagon

Stimulation

Hypoglycemia

Autonomic activation (exercise)

Increased plasma amino acids

Inhibition

Hyperglycemia

Insulin

somatostatin


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Somatostatin

Structure: polypeptide

Effects

Depress insulin and glucagon secretion

Decreased stomach motility, GI absorption

Extends time over which food is assimilated into tissues

Recall it is also known as the growth hormone

inhibitory hormone from the hypothalamus


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Somatostatin

Stimulation

Increased plasma glucose, amino acid, and FA

levelsGI hormones (gastrin, secretin, cholecystokinin,

GIP)

Inhibition

Decreased plasma glucose, amino acid, FA

levels


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Calcium & Phosphate Homeostasis

Major Factors influencing Ca and PO4

Parathyroid hormone

CalcitoninVitamin D

Intestinal absorption rate

Renal excretion rateBone mineral uptake/release


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Calcium

ECF concentration very tightly controlled

Ca functions:

Muscle contraction

Nerve impulse transmission Blood clotting

Cellular signaling

Bone matrix

Hypocalcemia Tetany

Seisures

C l i


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Calcium Hypercalcemia

CNS depression

Decreased reflex activity

Constipation

Normal Calcium Distribution

0.1% in ECF/plasma

1% in cells

99% in bones

Plasma Calcium 50% ionized calcium 41% protein-bound calcium

9% Ca complexed to anions


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Phosphates

Not as tightly controlled

Phosphate distribution

85% in bones14-15% in cells

< 1% in ECF


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Phosphates

Forms HPO4

-2, H2PO4- depending on pH

Functions

Bone matrix

Intracellular buffer

Renal tubular buffer

Phosphorylation (ATP, enzymes, etc.)

Hyper/hypo phosphatemia

Not generally significant except phosphate depletionmay lead to bone demineralization.


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Calcium Exchange

See figure 79-3 of the textnote therelationship between the following:

Dietary intake

Intestinal absorption and secretion

Excretion in feces

Kidney (filtration/reabsorption/excretion)

Cell calcium storesBone (deposition/absorption)

Bone


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Bone

Components: Osteoid (organic matrix) - Gives tensile strength

Collagen fibers

ground substance

Bone saltsgives compressive strength Hydroxyapatite crystals Ca10(PO4)6(OH)2

Non crystaline amorphous substances

CaHPO4.2H2O

Ca3(PO4)2.3H2O

Pyrophosphateinhibits HAP deposition in

tissues other than bone

Bone


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Bone

CalcificationosteoblastsOsteoid laid down

Osteoblasts encased osteocytes

Precipitation of bone saltsWoven bone low HAP, high amorphous

salts

Replaced by stronger bone (higher HAP)

Some amorphous salts always there (easily

exchanged)

Bone


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Bone

Bone absorptionOsteoclasts (macrophages, multinucleated)

Secrete proteolytic enzymes and acid

Tunnels into boneOsteoblasts fill in new bone (osteons,

Haversian)

Calcification and absorption= remodeling

Old bone is brittle

Bone can respond to stresses

Vitamin D


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Vitamin D See fig 79-6 in the text

Note the following

Activation cascade of vitamin D

Role of PTH

Inhibitory feedback


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Parathyroid Gland

Anatomy

4 small glands located posterior to the thyroid

gland, 2 on the left, 2 on the right Histology

Chief cellssecretes PTH

Oxyphil cellsfunction unknown


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Parathyroid Hormone (PTH)

Protein

Preprohormone prohormone PTH

Target tissuesBonecAMP dependant

KidneyscAMP dependant

Intestinesindirectly due to PTH effects onvitamin D


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Parathyroid Hormone

General Effects (see fig 79-10)

Increases blood Ca+2 levels

Mainly by bone absorptionDecreases blood phosphate levels

Mainly by increase excretion by kidneys

Parathyroid Hormone


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Parathyroid Hormone

Effects on bone - bone absorption Rapid phase (osteolysis)

mediated by osteocytes and osteoblasts (have PTH receptors)

causes release of calcium and phosphorus salts

Slow Phase mediated by osteoclasts

Activated indirectly via osteocytes/osteoblasts

Stimulate existing ostoclasts and increase development of new

osteoclasts

Breaks down osteoid as well as minerals

h id


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Parathyroid Hormone

Effects on Kidneys

decreases Ca excretion

increases phosphate excretion (which overridesincreased phosphate absorption from bone)

Occurs mainly in the distal tubules and

collecting tubules

Increases formation of 1, 25

dihydroxycholecalciferol

h id


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Parathyroid Hormone

Effects on Intestines

Because of the increased activated vitamin D, more

calcium and phosphate is absorbed in the intestines

PTH Regulation

Stimulated by decreased ECF Ca+2, histamine,

epinephrine

Inhibited by increases ECF Ca+2, calcitonin, 1,25

dihydroxycholecalciferol

Released in diurnal pattern

Calcitonin


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Calcitonin

Peptide released by parafollicular cells of thethyroid gland

Target tissue = bone

Effects

Decrease osteoclast activity

Decrease osteocytic osteolysis

Decrease formation of new osteoclasts Note- prolonged decreases in osteoclast activity leads to decreased osteoblast

activity, therefore no appreciable changes in calcium ion concentration

There is a very weak effect on kidney toincrease calcium excretion

H h idi


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Hypoparathyroidism

Calcium reabsorption from bones isdepressed

ECF Ca+2 levels decrease

Results in tetany

Causes

Autoimmune disorder against parathyroid gland

Thyroid surgery complication

genetic

Hyperparathyroidism


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Hyperparathyroidism

Extreme osteoclastic activity Increases ECF Ca+2 levels

Decreased phosphate levels

Weakened bones with frequent fractures

Cystic bone osteitis fibrosa cystica

Hyperparathyroidism


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Hyperparathyroidism

High plasma alkaline phosphatase Depression of the nervous system, muscle

weakness, constipation

Metastatic calcification

Kidney stones

Causes

Primarytumor, autoimmune

Secondaryvitamin D deficiency which leads tohypoclacemia and hypersecretion of PTH

Rickets (child)

Osteomalacia (adult)


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S t i


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Spermatogenesis

Occurs in seminiferous tubules

Spermatogoniagerminal epithelial cells

Sertoli Cells

Primary spermatocyte

First meiotic division

Secondary spermatocyte

Second meiotic division

Spermatid (haploid, 23X or 23Y)

Spermiogenesisspermatids mature spermatozoa

S t


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Spermatozoa

Head

Condensed nucleus

Acrosome (hyaluronidase, proteolytic enzymes) Tail (flagellum)

Microtubules (axoneme)

Cell membraneMitochondria (proximal)

Hormonal Control of


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Spermatogenesis Testosteronesecreted by Leydig cellsgrowth

and division of germinal cells

Luteinizing hormoneanterior pituitary

stimultes Leydig cells Follicle-stimulating hormoneanterior pituitary

stimulates Sertoli cells, which aid spermiogenesis

Estrogensconverted from testosteroneaids

spermatogenesis

Growth Hormonepromotes early division ofspermatogonia

M t ti St f S


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Maturation, Storage of Sperm

Epididymissome storage, develop some

motility (inhibited until ejaculation)

Vas deferensmost storage occurs here

Semen


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Semen

Spermatozoa (10%) Seminal Vesicles (60%)

Fructose, citric acid

Prostaglandins

Fibrinogen Prostate gland (30%)

Calcium, citrate, phosphate, clotting enzyme,fibrinolysin

Alkaline pH Bulbourethral gland

Mucus (lubricant)

In the Female Reproductive Tract Capacitation


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Capacitation

Final activation of sperm

Occurs in female reproductive tract

Acrosome reaction

Enzymes penetrate the corona radiata

(granulosa cells) and zona pellucidasurrounding the ovum

Fertilization - union of sperm and ovumpronuclei

Prevention of polyspermycorticalreaction


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The Male Sexual Act


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Stimulation

Sensory stimulation of glans penis and adjacentstructures pudendal nerve sacral plexus

spinal cord brain

Psychological statecan initiate or inhibit

sexual function.

The Male Sexual Act


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Stages

Penile erectionparasympatheticLubricationparasympathetic, urethral glands

and bulbourethral glands

Emissionsympathetic, contraction of vasdeferens, ampulla, prostate, seminal vesicles

Ejaculationsympathetic, addds contraction of

ischiocavernosus and bulbocarvernosus,

compress erectile tissueResolutionsexual excitement ceases

Androgens


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Androgens

Includes testosterone, dihydrotestosterone,androstenedione

Formed by the interstitial cells of Leydig, and

much less so in the adrenal glands Steroids derived from cholesterol

Transported by albumin or sex hormone-bindingglobulin

Most testosterone is converted todihydrotestosterone upon binding to tissues

Degraded in liver to products excreted in urine


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Functions of Testosterone


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Other effects

Baldness

Acne

Muscle developmentprotein anabolism

Boneincrease in mass

Control of Secretion:

GnRH LH (and FSH) Leydig cells

testosterones

Female Reproductive System


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Female Reproductive System

Reproductive tract

Vagina

Uterus Cervix

Body

Fundus

Ovaducts (uterine tubes, Fallopian tubes) Fimbriae, ampulla, isthmus

Ovarian Cycle


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Ovarian Cycle

Follicular phase (day 1-13)

Primordial follicleeach cycle, 8-12 follicles undergothe following development

Primary follicle Secondary follicle (vesicular follicle)

Tertiary follicle (mature, Graffian)

Follicle cells

Primary oocyte secondary oocyte

Granulosa cellssecrete estrogens

thecal cellssecrete some androgens

Ovarian Cycle


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Ovarian Cycle

Ovulationexpulsion of oocyte and corona

radiata

Usually only one follicle reaches this stage per cycle

Occurs about day 14 of the female reproductive cycle

Triggered by LH surge (FSH surge less important)

Luteal phase

Development of corpus luteum Secretes estrogens and progesterone

Ends with involution

Uterine Cycle


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Uterine Cycle

Day 1-5menstrual phase

Due to lack of progesterone (and estrogen)

from involuted corpus luteum

Vasospasm of endometrial blood vessels

Necrosis of endometrium

Uterine contractions (prostaglandins)

Uterine Cycle


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Uterine Cycle Day 6-13proliferative phase

Due mainly to estrogens

Re-epithelialization and growth in thickness

Day 14-26Secretory phase

Due mainly to progesterone Endometrial swelling

Secretory development

Blood vessels and glands become tortuous

Day 27Ischemic phase Lack of nutrients/oxygen due to vasospasm leads to

necrosis and menstruation ensues

Estrogens


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Estrogens

Secreted by ovaries (and adrenal cortex), and

placenta


Types

-estradiol (most significant)

Estrone

Estriol Transportalbumin, estrogen-binding globulins

Estrogens Functions


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Estrogens - Functions

Reproductive tract

uterus, vagina, oviducts, and external genitalia increasein size

Vaginal epithelium thickens Breast

Development of stromal tissues of breast

Development of extensive duct system

Fat deposition In conjunction with prolactin and progesterone milk

production

Estrogens Functions


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Skeleton

Increased osteoblastic activity

Union of epiphysesAfter menopause, decreased estrogen linked

with osteoporosis

Protein deposition

Weakly causes protein anabolism but much less

so than testosterone

Estrogens Functions


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Fat deposition

In subcutaneous tissues

In breastsThighs and buttocks

Hair

Axillary and pubic hair is more due toandrogens from adrenal cortex than due to

estrogens


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Progestins


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Progestins

Secreted by ovaries especially in latter halfof ovarian cycle


Types

Progesterone (most important)

17--hydroxyprogesterone

Transportalbumin and progesteronebinding globulins

Progesterone - Functions


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Progesterone - Functions

Uterus

Promote secretory changes in uterus in last of uterine

cycle

Decreases uterine smooth muscle activity

Uterine tubes

Increases secretions

Breasts Lobule and alveoli development

With prolactin milk secretion

Regulation of Female


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Reproductive Cycle GnRH

Secreted by the hypothalamus in a pulsitile fashion

Stimulates secretion of FSH and LH

FSH and LH FSHfollicle stimulating hormone

LHluteinizing hormonestimulates ovulation

Estrogen in small amounts inhibits their release

Estrogen in large amounts increases release??, or inconjunction with progesterone? preovulatory surge.

Inhibin secreted by the corpus luteum inhibits release

Puberty and Menarche


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Puberty and Menarche

Puberty

caused by increase in FSH and LH secreted by

the anterior pituitary

Begins at about 8 y.o.a.

Menarchefirst menstrual period, 11-16

y.o.a.

Menopause


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Menopause

Around 40-50 y.o.a.

burning out of the ovaries decrease inestrogens as number of follicles dwindle.

Symptoms

Hot flashes

Dyspnea

Irritability

Fatigue

Anxiety

Decreased strength and calcification of bones

Maturation of Ovum


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Maturation of Ovum

Ovary

Primary oocyte in follicle

Secondary oocyte following meiosis I

Generation of first polar body

Ovulation

Ovum + granulosa cells (corona radiata)

Begin but not finish meiosis II

Entrance into oviduct Fimbriated endcilia activated by estrogen

Travel to ampulla of oviduct

Fertilization


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Fertilization

Sperm transport

Sperm motility (flagellum)

Uterine and oviduct contractions Prostaglandins in semen

Oxytocin release in female during intercourse

Sperm reach ampulla = typical site for

fertilization

Fertilization


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Fertilization

Steps in fertilization

Acrosome reaction (sperm) digest corona radiata andzona pellucida

Fusion of sperm and ovum membranes Ovum response

Complete meiosis II, form second polar body

Zona reactionprevents polyspermy

Fusion of male and female pronuceirestore diploid

number

Sex determinationXX vs. XY


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Implantation


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Implantation

5-7 days post ovulation

Uterine milk

Trophoblast cells secrete proteolyticenzymes burrow into uterine epithelium

Trophoblast + uterine tissue placental

development

Nutrition of Embryo


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Nutrition of Embryo

Endometrial glands store glycogen, protein, lipidsin decidual cells

Digested and absorbed by trophoblast

(syncytiotrophoblast) Progesterone maintains endometrium, and

promotes gland secretion

So called trophoblastic nutrition last about 8

weeks until substantial placental development hastaken place.

Nutrition of Embryo/Fetus


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Nutrition of Embryo/Fetus

Placenta (begins functioning about 8 weeks postfertilization)

Trophoblastic cords (syncytiotrophoblast) allow

penetration of maternal blood vessels Maternal blood fills spaces called lacunae

(sinuses)

Cytotrophoblast develops into villi containing

embryonic/fetal blood vessels Formation of maternal bloodfetal blood barrier

Placental Transfer


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Placental Transfer

Oxygen Simple diffusionO2 gradient

Maternal PO2 = 50 mm Hg

Fetal PO2 = 30 mm Hg

Hemoglobin saturation in fetus remains high despitelow partial pressure of O2 because:

Hemoglobin Fhigher affinity (O2-Hb curve is further to theleft)

High concentration of fetal Hb

Bohr effectas CO2 (and acid) is transferred to mother, HbFbinds more oxygen, and HbA (mother) binds less O2.

CO2simple diffusion

Placental Transfer


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Placental Transfer

Nutrients

Facilitated diffusion (especially glucose)

Simple diffusion (most nutrients, electrolytes) Waste

Simple diffusion of urea, uric acid, creatinine

etc.

Hormones and Pregnancy


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Hormones and Pregnancy

Human chorionic gonadotropin (hCG)

Secreted by syncytiotrophoblast cells of the

embryo starting at implantation

Serum levels are highest at about 10-12 weeks

of pregnancy, then taper off

glycoprotein

Human Chorionic Gonadotropin


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Human Chorionic Gonadotropin

Functions

Prevents involution of corpus luteum

Corpus secretes more progesterone and estrogen

Prevents menstruation Decidua cells swell

Stimulates interstitial cell development in malefetuses

Secretes more testosterone

Male develops male sex organs

Placental Estrogens


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ce s oge s

Secreted by syncytiotrophoblast

Toward end of pregnancy, estrogen is 30X normal

Function

Enlargement of mothers uterus

Enlargement of mothers breasts and growth of breast

ducts

Enlargement of external genitalia Relaxation of SI and pubic joint ligaments

Mitogenic effect on fetus

Placental Progesterones


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g

Secreted by syncytiotrophoblast

Secretory rate 10X normal

Replaces corpus luteum as primary sourceof estrogens

Functions

Decidual cell development in endometrium

Decreases contractility of pregnant uterus

Promotes breast development

Human Chorionic

S t t i (hCS)


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Somatomammotropin (hCS)

a.k.a. human placental lactogen

Secreted by placenta starting at 5th week

Functions (not well known)May aid breast development

May have similar effects to growth hormone

Decreases insulin sensitivity in mother


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Endocrine Alterations in

P


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Pregnancy

Pituitaryenlarges, increases corticotropin,

thyrotropin, and prolactin production

Adrenal cortexincreased glucocorticoids,aldosterone

Thyroidincreased thyroxine

Parathyroidincreased parathormone

Pregnancy


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g y

Weight gain

Average 24 lbs

7 lbs fetus

4 lbs amniotic fluid, placenta, fetal membranes 2 lbs uterus

6 lbs blood, extracellular fluid

3 lbs fat

Increase in appetitecan increase weight gaineven more if mother isnt careful.

Pregnancy


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g y

Increased metabolic rate

Nutrition

Ironfor baby and mothers extra bloodVitamin Dfor calcium

Vitamin Kfor clotting factors

Increased blood volume (1-2 liters) Increased CO

Pregnancy


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g y

Increased respiratory rate (due to increasedmetabolism as well as effects of uterus against diaphragm)

Amniotic fluid

From fetal renal excretion

Amniotic membrane

Turnover every 3 hours

Preeclampsia, Eclampsia


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p , p

Hypertension, proteinurea

Excess salt and water retention

Arterial spasm in kidneys, brain, and liver Due to hormones?, autoimmunity?, allergy?

Eclampsia (coma, death) is severe form of

preeclampsia that occurs shortly beforebirth

Parturition


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Increase in uterine activity

Estrogen/progesterone ratio

Oxytocin

Stretch of uterine smooth muscle

Cervical stretch/irritation Braxton Hicks contractionsweak periodic

contractions before true labor begins

Labor

Positive feedback??? Cervix pressure = reflex uterine contractions ,

pituitary secretion of oxytocin

Parturition


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Abdominal musclereflexively contract due to

painful stimuli from uterus and birth canal.

Stages of labor

Firstcervical dilation and effacement(8-24 hours

w/ first pregnancy), amnion rupture

Secondmovement of fetus through cervix and vagina

(30 min2 hrs w/ first pregnancy)

Uterine involution

Lasts 4-5 weeks, facilitated by lactation

Lactation


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Growth of ductal systemestrogen (and otherhormones GH, prolactin, glucocorticoids, insulin)

Lobule-Alveolar systemprogesterone

Initiation of lactationprolactin, human chorionic

somatomammotropin Colostrum (proteins, lactose, little fat)secreted

immediately before and after parturition

Milkafter estrogens and progesterones decrease post

partum. Nursingstimulates prolactin secretion, maintains

milk production

Lactation


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Suppresses female ovarian cycles

Inhibits GnRH secretion from hypothalamus

Ejection (let down)

Oxytocinsuckling or emotional signals increase

oxytocin secretion from posterior pituitary.

Milk compositionwater, fat, lactose, casein,

lactalbumin, ash (minerals), antibodies,

neutrophils, macrophages

Fetal Physiology


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y gy

Growth

1st two weeksplacental , membrane development

>>>> embryo development

Thereafter, length is roughly proportionate to age The rate of weight gain increases with age of fetus

Circulatory system

Heart begins beating at about 21 days

Red cellsyolk sac and placenta liver spleen

bone marrow


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Fetal Physiology


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GI tract

Ingest and absorb amniotic fluid

Meconiummucus, bile, amniotic residue

Kidneys

Excretes urine during last half of pregnancy

Control of electrolyte and acid/base balance is

poor

Fetal Physiology


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Metabolism

Mainly utilize glucose for energy

Storage of fat and protein (from glucose sources)

Calcium and Phosphate - most is accumulated duringossification (last 4 weeks of gestation)

Ironaccumulates rapidly for hemoglobin synthesis

Vitamins

B12 and folatefor RBC, nervous system, growth

Vitamin Cfor bone matrix and connective tissue

Vitamin Dbone growth (calcium absorption by mother) Vitamin Efunction unclear, deficiency leads to spontaneous

abortion

Vitamin Kblood clotting

Time of Birth


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Onset of breathing Slightly asphyxiated state during birth

Sensory stimuli from cooled skin at birth

Hypoxia can occur due to compression of umbilicalcord, placental separation, anesthesia, excessive uterinecontractions

Infant can tolerate up to 10 minutes without O2 Lung Expansionrequires 60 mm Hg negative

pressure to inflate lungs the first time, by 40 minutes,

respiration is near normal Respiratory distress syndromeprematurity and lack of

surfactant

Time of Birth


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Changes in circulation Systemic circulationincreased vascular resistance due

to loss of circulation through placenta

Pulmonary circulationdecreased vascular resistancedue to lung expansion, increased O2 also causes

vasodilation of pulmonary vessels

Closure of foramen ovaledue to above pressurechanges

Closure of ductus arteriosuspressure changes reverse

blood flow through ductus, and increases oxygen andprostaglandins cause constriction

Closure of ductus venosusforces more blood throughliver sinusoids (prepares liver for functional activity)


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Miscellaneous Problems


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Liver immaturity

Little bilirubin conjugation (see above)

Little plasma protein production edema

Deficient gluconeogenesis

low blood glucose Little blood clotting factors abnormal coagulation

Body temperature

Surface area/ volume ratio loss of body heat

Immunity Passive immunity from mother (lasts 6 months)

Growth and Development Birthsuckling


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1 monthsmiles 2 monthsvocalization (other than crying)

3 monthshead control

3 monthshand control

5 monthsroll over 6 monthssitting

7 monthcrawling

8 monthswell developed grasp

9 th ll

Documents

Endocrine and Reproductive Physiology