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PHGY 210 – Endocrinology
Lecture 1
1. Endocrine signaling
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
hormone secretion into the blood by endocrine gland
hormone transported by the blood to a distant target site
Neuroendocrine Signaling
8/20/2013 11:04:00 AM
Paracrine Signaling
Autocrine Signaling
Communication by hormones (or neurohormones)
1. SYNTHESIS of the hormone by endocrine cells
2. RELEASE of the hormone by endocrine cells
3. TRANSPORT of the hormone to target site by blood stream
4. DETECTION of the hormone by a specific receptor protein on target cells
5. A CHANGE in CELLULAR METABOLISM triggered by the hormone-receptor
interactions
6. REMOVAL OF THE HORMONE, which often terminates the cellular response
Hypothalamic-Pituitary Signaling
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via blood vessels of pituitary stalk
hypothalamic-hypophyseal portal system
o from hypothalamus to anterior pituitary
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hypothalamic neurohormones either activate or inhibit activity of one of the six types
of hormone-producing cells in the anterior pituitary
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called either releasing hormones (RFs) or inhibiting hormones (IFs)
Properties of Hormone Receptors
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SPECIFICITY: recognition of single hormone or hormone family
AFFINITY: binding hormone at its physiological concentration
SHOULD SHOW SATURABILITY: finite number of receptors
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MEASURABLE BIOLOGICAL EFFECT: a measurable biological response due to
interaction of hormone with its receptor
Receptor Regulation

Receptors can be upregulated either by
o Increasing their activity in response to hormone
o Increasing their activity in response to their synthesis

Receptors can be downregulated either by
o Decreasing their activity
o Decreasing their synthesis
3 mechanisms by which a hormone can exert effect on target cells
1. Direct effect on functions at the cell membrane
2. Intracellular effects mediated by second messenger systems
3. Intracellular genomic signaling
Lecture 2
8/20/2013 11:04:00 AM
A. Feedback control of hormone secretion
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Hormone secretion is regulated by feedback mechanisms
An excess of hormone, or excess of hormonal activity, leads to a diminution of
hormone secretion
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A deficiency of hormone leads to an increase in hormone secretion
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Ca acts in a negative feedback loop to regulate plasma Ca levels
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CRH: corticotropin release hormone
ACTH: adrenocorticopic hormone
Cortisol (glucocorticoid)
B. Endocrine glands and their secretions
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Pituitary Gland
1. Anterior pituitary : endocrine tissue
2. Posterior pituitary : neural tissue
Signaling between hypothalamus and the pituitary
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FSH: follicle stimulating hormone
LH: luteinizing hormone
IGF-1: insulin-like growth factor 1
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Prolactin-inhibiting hormone (PIH) is like dopamine
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Posterior Pituitary Gland
o Outgrowth of hypothalamus connected by the pituitary stalk
o Secretes oxytocin and vasopressin
o Oxytocin and vasopressin synthesized in two hypothalamic nuclei
 Supraotic
 Paraventricular
o Prohormones processed in secretory granules during axonal transport
o Mature hormones liberated from the carrier molecule, neurophysins
o Circulating half lives: 1-3 minutes

Oxytocin
o Males: no known function, but secreted by posterior pituitary
o Females:
1. Parturition
 uterus extremely sensistive to oxytocin at end of pregnancy
 dilation of uterine cervix by fetal head causes reflex release of
oxytocin
 causes uterus to contract, assists the expulsion of fetus and
placenta
2. Milk Ejection
 in lactating mother, response to the stimulus of suckling
 oxytocin causes milk filled ducts to contract and squeeze milk
out

Thyroid Gland
o Colloid: major component is Thyroglobulin
o Contains thyroid hormones (T3 & T4)
o T3 & Y4 are split off the thyroglobulin, enter the blood where they bind to
special plasma proteins
o Synthesis of thyroglobulin under control of TSH of pituitary gland
o Thyroglobulin provides a type of storage for T3 & T4 to release

Thyroid hormones contain Iodine
o Availability to iodine is limited to terrestrial vertebrates
o Thyroid follicular cells are able to trap iodide and transport it across the cell,
against a chemical gradient (active transport)

Synthesis of thyroid hormones
o Iodine (I2) used for iodination of tyrosine residues of thyroglobulin (TGB) 
MIT & DIT
o Oxidative coupling of 2 DIT  T4
o Oxidative coupling of 1 DIT + 1 MIT  T3
o T3 & T4 are stored/linked to TGB
o Rate of all steps of formation are increased by TSH

Control of Thyroid Activity
o Without TSH
 Very little turnover of thyroid hormones
o Synthesis/release of TSH controlled by TRH
o When T3 & T4 in blood increase, they exert a negative feedback at both
hypothalamic and pituitary levels to decrease release of TRH and TSH
o TSH interacts with specific receptors on follicular cells, leading to increased
production of T3 & T4
C. Iodine deficiency
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When supply is deficient, synthesis of thyroid hormones decreases and T3 & T4
decrease in circulation
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Release of TSH increases, thyroid follicular cells are constantly stimulated
Thyroid enlarges, may form a visible lump = Goiter
The enlarged thyroid is unable to synthesize biological active thyroid hormones =
Non-toxic goiter
Molecular mechanisms of action of thyroid hormone
1. T3 & T4 enter target cell nucleus, bind to their cognate nuclear receptor. Alters
transcription of specific genes/proteins.
2. may induce effects by interactions with plasma membrane and mitochondria. A
specific receptor for T3/T4 located in inner mitochondrial membrane. Not blocked by
inhibitors of protein synthesis.
It is independent of protein synthesis.
3. T3/T4 act directly at plasma membrane and increase uptake of amino acids.
It is independent of protein synthesis.
Abnormalities of Thyroid Function
1. Not enough
o Hypofunction of the thyroid gland (Hypothyroidism)
o Low levels of thyroid hormones
2. Too much
o Hyperfunction of the thyroid gland (Hyperthyroidism)
o High levels of thyroid hormones
Hypothyroidism
A) Primary hypothyroidism (Myxedema)
o Level of the thyroid: inability to synthesize active thyroid hormones
o More common in women than men; appears ~ 40-60 years of age
o Causes
 Atrophy of the thyroid

Autoimmune thyroiditis
 Destruction by antibodies against cellular components of
thyroid (Hashimoto’s disease)
 Goistrous Hypothyroidism or Non-Toxic Goiter
 Bloackage in a step of T3/T4 synthesis
 Thyroid gland increases in size, non-toxic goiter formation
B) Secondary hypothyroidism
o Level of the pituitary: synthesis of little or no TSH
C) Tertiary hypothyroidism
o Level of hypothalamus: synthesis of little or no TRH
D) Infantile hypothyroidism
o Absence of thyroid gland or incomplete development of thyroid gland at birth
o Fetus is fine, uses mother’s T3/T4
o Child is born, develops growth retardation (Dwarfism) and mental retardation
(Cretism)
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Treatment
o Administration of thyroid hormones
Hyperthyroidism
A) Primary hyperthyroidism
1. Toxic Diffuse Goiter (Graves Disease)
 autoimmune disease, presence of substance produced by lymphocytes
(LATS), it mimics TSH, stimulating release of T3/T4
 constant stimulation by LATS increases mass of thyroid, formation of
Toxic Goitre
2. Thyroid Adenoma (Thyroid cancer)
 synthesis of thyroid hormones independent of TSH stimulation
B) Secondary hyperthyroidism
o Level of anterior pituitary: no negative feedback from increased levels of
T3/T4 and synthesize autonomously TSH
o Often due to pituitary tumor
C) Tertiary hyperthyroidism
o Level of hypothalamus: no negative feedback of high T3/T4 to decrease
synthesis of TRH
o Often due to hypothalamic tumor

Treatment
1. surgery & replacement therapy
 Administration of thyroid hormones
2. administration of radioactive iodide
 Concentrates in the cells of thyroid follicles and destroys them
3. Administration of antithyroid drugs
 Propylthiouracil
 Blocks addition of iodine to TGB
 Must be careful not to use too much and cause hypothyroidism
Lecture 3
8/20/2013 11:04:00 AM
Endocrine control of Calcium Homeostasis
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Importance of Ca
o Component of skeleton
o Normal blood clotting
o With Na and K, maintains transmembrane potential of cells
o Excitability of nervous tissue
o Contraction of muscles
o Release of hormones and neurotransmitters
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Concentration in cellular/extracellular fluid ~ 10mg/100ml
o In circulation: 50% free, 50% bound to Albumin
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~ 99% of the body’s Ca is in bone
o part of it is loosely bound
o bone is a Ca reservoir
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Hormonal Control
o Maintenance of plasma calcium is achieved by exchanging between bone and
plasma under influence of hormones
o Hormones also affect intestinal absorption of Ca and excretion by kidneys
Important hormones
1. PTH
o Protein
o produced by parathyroid glands
o increases levels of Ca
2. Calcitonin
o protein
o produced by parafollicular or C cells of the thyroid gland
o lowers levels of Ca
3. Vitamin D
o increases the levels of Ca
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Ca cycle
o Obtained in diet
o Absorbed from digestive tract (duodenum/upper jejunum)
 it’s absorption is increased by Vit D and PTH
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From the plasma
o Some deposited in bone
 Calcitonin increases it
o Through kidney/urine
 Calcitonin increases it
o When plasma concentration is < 10mg/100ml, PTH stimulates reabsorption of
Ca from kidney, and removal of Ca from bone (bone resorption)
o Stable concentration: exchanging Ca between bone and plasma
Parathyroid Hormone
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Secreted by parathyroid chief cells
4 parathyroid glands
removal of plasma thyroids: severe drop in plasma Ca levels, causing tetanic
convulsions and death
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PTH structure
o Synthesized as part of preproparathyroid hormone, which undergoes
proteolytic cleavage to produce PTH
o Very short half life
Functions of PTH
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Increase the concentration of plasma Ca
1. Bone resorption
2. Kidney
3. Vitamin D synthesis
4. Gut
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Control of PTH release
o Directly by circulating concentrations of Ca
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Mechanism of PTH activity
o Binds to cognate receptor on target cells
Problems with Parathyroid Gland Function
1. Hypofunction
o Low levels of PTH
o Symptoms: low plasma Ca, production of VitD decreased, tetany
o Treatment: administration of VitD and Ca supplements
2. Hyperfunction
o Producing too much PTH
o Symptoms
 High production of 1,25D3
 High PTH stimulates bone resorption and Ca reabsorption by kidney
 1,25D3 increases Ca absorption from intestines
 elevated Ca levels
 formation of kidney stones
o Treatment: surgery to remove the affected parathyroids, replacement therapy
of 1,25D3 and Ca
Vitamin D
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Available from limited dietary sources
Synthesized from cholesterol metabolite
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Synthesis
1. UVB light in skin
2. 25-hydrozylation in liver
3. 1-hydroxylation in kidney & several peripheral tissues  1,25D3
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Physiological function
1. primary: increase Ca absorption from intestine
2. regulates immune system  anti-inflammatory
3. anticancer properties
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Regulation of Vit D synthesis in kidney
o Increased in conditions of low calcium, when PTH is also increased
o Depressed by high calcium
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Vit D deficiency and deficient bone mineralization  Rickets in growing individuals,
Osteomalacia (soft bone)
Calcitonin
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Manufactured in parafollicular cells of thyroid gland
Lowers plasma Ca by promoting transfer of Ca from blood  bone, increasing
urinary excretion of Ca
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Rise in plasma Ca increases release of Calcitonin (vice versa)
Of lesser importance than PTH and 1,25D3
It’s biological importance in man is limited
Adrenal Glands
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Heavier in male than females
2 types of tissue: Cortex & Medulla
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Cortex
o large-lipid containing epithelial cells
o derived from mesoderm
o produces steroid hormones
 glucocorticoids (cortisol)
 mineralocorticoids (aldosterone)
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Medulla
o Chromaffin cells fine brown granules when fixed with potassium bichromate
o Derived from neural crest
o Produce
 Catecholamines
 Epinephrine
 Norepinephrine

Some peptide hormones
 Enkephalins, dynorphins, atrial natriuretic peptides
Adrenal Cortex
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3 different layers
o Zona glomerulosa
 Mineralocorticoids (aldosterone)
o Zona fasciculate
 Glucocorticoids (cortisol)
o Zona reticularis
 Glucocorticoids
 Progestins
 Androgens
 Estrogens
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Synthesis of adrenal steroids contolled by ACTH
Action of steroid hormones
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Regulate the transcription of hormone/receptor-specific target genes
Physiological Roles of Adrenal Hormones
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Aldosterone
o Na metabolism
o Increases reabsorption of Na by kidney
o Affects plasma concentration of K and H
o Loss of K and H in urine balance reabsorption of Na
Glucocorticoids
1. Salt retention
o less effective than aldosterone
2. Effects on protein and carbohydrate metabolism
o gluconeogenesis
o glucose oxidation
o increased blood glucose levels  increased insulin secretion
3. Lipid metabolism
o increase levels of lipolytic enzymes in adipose tissue cells
o ex: Epinephrine
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excess of glucocorticoids leads to hyperlipidemia & hypercholesterolemia
4. Anti-inflammatory and immunosuppressive actions of glucocorticoids
o reduce inflammatory responses
o causes atrophy of lymphatic system
 glucocorticoids are used in organ transplant
o decrease histamine formation  decrease allergic reactions
5. Effects on bone
o decrease protein matrix of bone through protein catabolic effect
o increased loss of Ca from bone  osteoporosis
Control of glucocorticoid secretion
Mechanism of action of ACTH
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Binds to specific ACTH receptor on membranes of zone fasciculate & reticularis cells
Stimulation of adenylyl cyclase  increased production of cAMP
Activates steroidogenic enzymes  increased synthesis/release of steroid hormones
Minimum at night, maximum in the morning
Rhythm independent of sleep, abolished by stress and Cushing’s disease
Glucocorticoids and stress-response
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Advantages to release of cortisol during stress
o Provides energy and amino acids through the breakdown of tissue proteins
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Disadvantages to release of cortisol during stress
o Cortisol inhibits wound healing
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Prolonged stress would maintain constantly high levels of glucocorticoids, which
could lead to increased blood glucose, decreased immune response, loss of bone, etc.
Lecture 4
8/20/2013 11:04:00 AM
Pathophysiology of Adrenal Cortex
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Addison’s Disease : hypofunction
o Failure of the adrenal cortex to produce adrenocortical hormones
o May involve total destruction of gland
o Mostly due to atrophy of adrenal glands
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Cushing’s disease : hyperfunction
o Hyperplasia of the adrenal cortex due to increased circulating levels of ACTH
o Excessive production of glucocorticoids and mineralocorticoids
The Pancreas
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99% is exocrine and secretes the digestive enzymes
scattered within exocrine, small endocrine structures, the Islets of Langerhans –
compact mass of cells with good vascularization
o 60% beta cells
 synthesize insulin
o 25% alpha cells
 synthesize glucagon

Insulin & glucagon: control glucose concentration in blood
o Insulin is more important than glucagon
Action of Insulin
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Acts primarily to decrease blood glucose
Glucose does not diffuse readily into most cells – must be transported
A) liver and muscle cells: converted to fat, stored for later use
B) adipose tissue: converted to fat, stored for later use
C) other cells: oxidized to produce energy

Insulin receptor: membrane receptor, stimulates insertion of glucose transport
proteins stored in cytoplasm into plasma membrane – increases glucose uptake
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Insulin Deficiency
o When beta cells are destroyed  Diabetes Mellitus, glucose accumulates in
circulation
o Occurs even when no glucose in diet  increased gluconeogenesis
o FFA becomes principal source of energy – increased lipolysis
 Fat inefficiently used – incomplete breakdown  increased circulating
acetoacetic acid, beta-hydroxybutyric acid, and acetone
 decreased blood pH, diabetic coma, death
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Other symptoms of Diabetes Mellitus
> 180 mg% glucose spills over into urine  glycosuria
o Loss of water in urine  polyurea – dehydration & polydipsia
o Treatment: administration of insulin, correction of electrolyte imbalance
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Causes of Diabetes Mellitus
o Adults: deficiency of insulin (type 1 insulin-dependent) or
hyporesponsiveness to insulin (type 2 insulin-independent)
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Type-1 insulin-dependent Diabetes Mellitus
A) Destruction of beta cells of pancreas
 Synthesis of insulin does not occur
 Treatment: administration of insulin, proper diet
B) Defective insulin release
 Drugs stimulating insulin released, proper diet
o Blood glucose 20-30 mg/100 ml is not sufficient for the brain 
hypoglycemic coma
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Type 2 insulin-independent Diabetes Mellitus
o Insulin levels normal or abnormally high
o Insulin resistance due to decreased number of insulin receptors on target cells
o Associated with obesity – prolonged high insulin levels decrease number of
receptors (downregulation)
o Treatment: proper diet and exercise
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Juvenile Diabetes Mellitus
o Childhood
o Insulin-dependent
o Beta-cells of pancreas do not produce insulin
o Treatment: administration of insulin
Measurement of Glucose Tolerance
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Glucose tolerance test
o Glucose tolerance is decreased in diabetes and increased in hyperinsulinism
o After overnight fast; 0.75 – 1.5 g glucose/kg body weight given
o Blood taken before administration at 30-60 min intervals for 3-4 hours
o Glucose is measured
o Blood glucose for a normal individual
 After 1 hour: 80 mg/100 ml – 130 mg/100 ml
 After 2-3 hours: returns to normal
o Blood glucose for a diabetic
 The increase in glucose is greater
 Returns to normal more slowly
Control of Insulin Secretion
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Beta-cells respond to levels of blood glucose, secreting little or no insulin when blood
high (and vice versa)
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Release of Gastrin and vagal impulses to the beta-cells induce insulin release
o Insulin leaves pancreas before the rise of blood glucose during a meal
Glucagon
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Synthesized and released by alpha-cells of pancreas
Raises blood sugar by promoting glycogenolysis and gluconeogenesis
Adipose tissue: glucagon increases rate of lipolysis  increased FFA in circulation
Glucagon not as important as insulin
Other hormones that increase blood glucose
o Cortisol
o Epinephrine
o Nor-epinephrine
Growth Hormone
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Produced by anterior lobe of pituitary
Responsible for growth (aka Somatrotropin STH)
Increases protein synthesis by enhancing amino acid uptake by cells, accelerating
transcription and translation
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Increases rate of lipolysis, utilizes free FFAs as source of energy
o Direct effect of GH, not mediated by somatomedins
Somatomedins
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Produced by liver under stimulation of GH
Insulin-like growth factors I and II
May bind to insulin receptors
Insulin at high concentrations may bind to somatomedin receptors
Increase protein synthesis and stimulate growth
Control of GH release

Mediated by 2 hypothalamic neurohormones
A) GRH: stimulates growth hormone release
B) GIH: inhibits growth hormone release

GRH and somatostatin tightly regulated by integrated system of neural, metabolic,
and hormonal factors
Pathophysiology of Growth Hormone
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GH deficiency
o Youth; decreased physical growth

Excess of GH
o Youth; gigantism
o Adults; acromegaly – many bones get longer and heavier
Reproduction

Gonads serve 2 main functions
1) Gametogenesis – production of gametes
2) Secretion of sex hormones
 Male: testosterone (androgen)
 Female: estrogen & progesterone
Function of Estrogen in males
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Necessary for growth
Deficiency  osteoporosis
Control of Reproductive Function
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Gonads also produce Inhibin – feeds back on the anterior pituitary
I. Male Reproductive System: Function of Testes
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Production of mature germ cells (spermatogenesis) and steroid hormones
(steroidogenesis)
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Continuous renewal of germ cells, relative constant supply throughout life
Spermatogenesis takes place within seminiferous tubules of testes
Maturation into spermatozoon takes ~ 60 days
2 cell types critical for Maturation of Spermatozoa
1. Leydig cells
o located outside seminiferous tubules
o respond to LH by synthesizing androgens
2. Sertoli cells
o located within seminiferous tubules
o sperm maturation process – envelop the germ cells throughout their
development
o respond to FSH by synthesizing ABP and inhibin
Spermatogenesis
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Dependent on androgen concentrations within seminiferous tubules
o Must be 10X higher than [androgen] in circulation
o Presence of ABP ensures high [androgen] within seminiferous tubules
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Testicular androgen synthesis relation: 2 negative feedback loops
a) hypothalamic-pituitary-Leydig cells axis
 Leydig cells produce androgen, which inhibit release of GnRH, LH,
FSH
o b) Hypothalamic-pituitary-seminiferous-tubule axis
 non steroidal inhibin secreted by sertoli cells inhibits FSH release

NO (+) feedback in males
II. Female Reproductive System: Ovarian Function

Ovary
o Production of mature eggs, steroid hormones
 Regulate tract and influence sexual behavior
o Contain entire pool of eggs at birth – oocytes
o Oocytes surrounded by single layer of granulosa cells – make up primordial
follicles
 Fundamental reproductive unit of ovary
o Growth of primordial follicles into primary follicles begins by unknown
initiating event (independent of pituitary)
o Once initiated, growth controlled by gonadotropins and steroid hormones until
follicles either ovulate or degenerate (atresia)
Follicular growth: development of oocytes suitable for ovulation, and of new endocrine
organ
1. enlargement and differentiation of the oocyte, elaborates zona pellucida

2. granulose cells divide and increase to > 2 layers – primary follicles.
Influenced by FSH and estrogens
Estrogens important for expression of LH receptors on granulosa cells
3. Under influence of FSH and LH, primary follicle develops into secondary follicle,
which expresses receptors for FSH, estrogens, and LH
Appearance of follicular antrum, contains secretions for granulosa cells
4. Under influence of FSH and LH, granulosa cells elaborate follicular fluid, which
takes up the larger portion for the preovulatory follicle (mature follicle)

Note: as follicle matures primary  secondary, cells from ovarian stroma become
steroid producing cells – Theca cells. Theca interna and granulosa cells collaborate
for synthesis of higher amounts of estrogen.
Follicular development leads to…
1. Follicular Atresia
o Only 1 follicle will ovulate in each reproductive cycle
o Remaining secondary follicles degenerate
2. Ovulation
o Follicular rupture poorly understood
o Increase in intrafollicular pressure and proteolysis of ovarian wall of mature
follicle lead to ovulation
Luteinization (after ovulation)
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Ruptured follicle transformed into Corpus Luteum
o Secretes progesterone and estrogens
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Progesterone and Estrogens produced in large amounts for few days following
ovulation, but drop off unless implantation of fertilized ovum occurs
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Upon implantation, corpus luteum transformed into corpus luteum of pregnancy
o Responsible for synthesis of progesterone and estrogens, and creation of
proper endocrine environment for maintenance of pregnancy until
progesterone and estrogen synthesis by placenta established
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Luteolysis
o In absence of implantation, life span of corpus luteum limited
o Luteal regression may be induced by prostaglandins, which decrease LH
binding, and steroidogenesis
o Decrease of plasma progesterone and estrogen may be the trigger of initiation
of next reproductive cycle
Lecture 5
8/20/2013 11:04:00 AM
The Menstrual Cycle
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< day 1: endometrium thickens under influence of estradiol
Progesterone induces appearance of specialized glycogen-secreting glands
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Day 1: first day of detectable vaginal bleeding – deterioration of uterine endometrium
Bleeding begins when estradiol and progesterone levels are very low, when blood
vessels supplying endometrium constrict, reducing blood supply
Endometrium deteriorates, flows through cervix, into the vagina
Bleeding lasts ~ 5 days during which ovaries are endocrinologically inactive
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Low estradiol and progesterone  increased pituitary FSH secretion (lack of (-)
feedback loop)
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Decrease in non-steroidal inhibin  elevation in FSH release
FSH stimulates proliferation, production of estrogen, further proliferation
Day 8: 1 dominant follicle committed to further development, remaining degrade
Dominant follicle produces increasingly more estradiol, which stimulates uterine
endometrium proliferation
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Day 13: endometrium very thick, estradiol induces production of emdometrial
progesterone receptors
Estradiol effects on Brain and Pituitary
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Moderate estradiol concentrations
o (-) feedback on FSH release
o stimulate synthesis of LH by pituitary and increase sensitivity of pituitary to
GnRH  stimulates LH synthesis
o LH accumulates to high levels within pituitary due to inhibition of release

High estradiol concentrations
o Developing follicle, estrogen concentrations continue to increase
o Elevated estrogen concentrations stimulate LH release – LH Surge
o Day 14: small increase in FSH release occurs
o Stimulation of LH synthesis by estradiol, increased sensitivity of pituitary to
GnRH  increased LH synthesis = (+) feedback control mechanism
o Estrogens exert (-) feedback : decreased GnRH and LH release
(+) feedback: increased sensitivity of pituitary to GnRH and
increased LH synthesis
o At the ovary, follicle has become huge. LH surge causes the follicle to rupture
and ovum is ejected
Oral Contraceptives
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Contain estrogen and progesterone
Maintain moderate circulating levels to suppress the release of LH and FSH, prevent
ovarian follicle from maturing
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99% successful
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Luteal Phase
o No fertilization – egg degenerates, corpus luteum degenerates, lasts 14 days
o After 14 days, steroid levels drop, uterine endometrium degenerates,
menstruation begins and pituitary starts to increase its secretion of FSH
(restart cycle)
Fertilization and Implantation
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Spermatozoa deposited in vagina
Travels to oviduct and fertilizes an egg
Egg starts dividing to the stage of blastocyst during transport down to uterine lumen
After implantation
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Blastocyst  trophoblast (becomes placenta) & inner cell mass (becomes embryo)
Trophoblast starts to synthesize HCG, which has LH-like properties, stimulates
corpus luteum to continue secreting gonadal steroids
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12th week: endocrine function of corpus luteum take over entirely by placenta
fetal liver acquires important function in the synthesis of estriol (an estrogen)
placenta produces human chorionic somatotropin, progesterone, and relaxin
Pregnancy Test
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HCG quickly appears in blood and urine
Lactation
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Mature non-pregnant mammary glands (ductal)
o Onset of puberty, increasing levels of estrogen enhancement of duct growth
and duct branching, little development of alveoli
o Progesterone stimulates growth of alveoli
o Most breast enlargement due to fat deposition
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Pregnant mammary gland (lobulo-alveolar)
o Under influence of estrogen, progesterone, prolactin, human placental
lactagen, ductal and alveoli fully develop
o Milk production controlled by prolactin
o high estrogen levels inhibit secretion

Lactating Mammary Gland
o Levels of estrogen decrease, levels of prolactin remain high
o Nursing: under action of oxytocin, ducts contract to cause milk ejection
o Prolactin and oxytocin stimulated by afferent nerves from nipple
o Milk: water, protein, fat, and carbohydrate lactose, and antibodies. Possibly
viruses and drugs.

Lactational Amenorrhea
o Maintained nursing stimulates prolactin production, which inhibits secretion
of FSH

Menopause
o At end of reproductive period, most ovarian follicles have disappeared by
atresia
o Depletion of follicles results in loss of capacity for steroid (estrogen and
progesterone) hormone production by ovary
o Lack or estrogens: hot flashes, dry vagina, restlessness, bone loss
Eliminates (-) feedback loop, and rise in levels of FSH and LH
The constantly high levels of plasma FSH is an indicator of onset of
menopause
o Fertility cannot be restored by steroid replacement therapy
Nuclear Receptors
Mechanisms of signaling by nuclear and membrane receptors

Small lipophilic molecules
o Steroid hormones, cholesterol metabolites, bile acids, thyroid hormone, Vit A
metabolites, 1,25D3, FFAs, xenobiotics

Nuclear receptors exert physiological effects largely by regulating the transcription of
a receptor-specific subset of genes in the human genome  changes in the types and
concentrations of proteins present in target cells, altering cell function

First nuclear receptors identified for classical endocrine hormones
o Steroid hormones:
 Estrogen, progesterone, androgens, glucocorticoids, mineralocorticoids
o Thyroid hormones, VitD

Receptor-ligand interactions:
1. Lipophilicity of the ligand
2. High ligand-receptor specificity
3. High ligand-receptor affinity (low nM)

48 genes that encode nuclear receptors
Orphan Hormone Receptors

Genes encoding proteins that were novel members of specific classes of hormone
receptors but did not bind known classes of hormones
1. Hormones (ligands) carry signals that control many fundamental human
physiological processes. Existence of novel signaling molecules that control other
fundamental processes (orphans)
2. Nuclear receptor ligands are ideal candidates for drug development
PXR ligands and drug-drug interactions


PXR paralleled drugs that stimulate induce CYP3A activity in mice and humans
small molecule drug candidates can activate their own metabolism and the
metabolism of other drugs

candidate compounds that are potent activators of PXRs are eliminated from further
drug development
PPARs : control of lipid metabolism and adipogenesis


3 PPAR receptors: alpha, delta, gamma
name: peroxisomal proliferator-activated receptor derived from observation that
PPARs bind at high concentrations to classes of toxic compounds that caused
proliferation of peroxisomes in livers of rats (not observed in humans)
Lecture 6
8/20/2013 11:04:00 AM
PPAR-alpha


Most highly expressed in tissues that display high rates of FFA metabolism
PPAR-alpha bound peroxisomal proliferators, and certain types of FFAs and their
metabolites

Ligand-activated PPAR-alpha receptors stimulated expression of several genes
controlled fatty acid metabolism

.:. some fatty acids can control their own metabolism through PPAR-alpha by
inducing the expression of genes encoding metabolic enzymes required for fatty acid
catabolism
PPAR-gamma
 Orphan receptor
 Most highly expressed in adipose tissue, intestine, and spleen
 Thiazolidinedione (TZD) has a high affinity ligand for PPAR-gamma
 TZD originally developed as antidiabetic drugs
PPAR-gamma and Insulin Resistant Diabetes


PPAR-gamma function essential for normal adipogenesis
TZDs lower the circulating levels of fatty acids, leaving less fat to be used as fuel,
higher dependence of glucose as fuel

Enhances capacity of muscles to burn glucose and represses capacity to burn fat

Very effective in obese people with insulin resistance
FXR: Control of bile acid metabolism

Cholesterol metabolism control:
1. A feed-forward mechanism; oxysterols activates productions of CYP7A,
the enzyme responsible for conversion to bile acids
2. A feed-back mechanism; elevated levels of bile acids inhibit further bile
acid synthesis

FXR as a bile acid receptor
o Orphan receptor FXR highly expressed in tissues where bile acids function
o FXR activated by primary bile acid chenodeoxycholic acid

Bile acids
o Produced in liver
o Secreted into bile ducts and transported to small intestine
o Represent solubilized excitable forms of cholesterol
o Facilitate absorption of fats and fat-soluble vitamins in the intestine
1. Bile acid-bound FXR repressed expression of CYP7A, which encodes the ratelimiting enzyme in cholesterol metabolism to bile acids (feedback mechanism: bile
acids regulate cholesterol metabolism)
2. Elevated bile acid levels were known to induce expression of intestinal bile acid
binding protein
Vitamin D

Provitamin D3  (UV-B/Skin) Vitamin D3  (25-hydroxylation/Liver) 25-hydroxyvitamin D3 (major circulating form)  (1-hydroxylation/peripheral tissues) 1,25dihydroxy-vitamin D3  Vitamin D receptor (RESTART)



Vitamin D is obtained from UV radiation from the sun
Low levels of vitamin D during the winter
Lighter skin gets more vitamin D than darker skin

3 types of diseases have demonstrated north-south gradients
1. Certain types of cancer (digestive and leukemia)
2. Autoimmune diseases (multiple sclerosis)
 cells of the immune system become responsive to 25D3 after sensing
the presence of bacterial cell wall components
 treatment of cells with 1,25D3 induces secretion of antibacterial
activity in the form of antimicrobial proteins
3. Infectious diseases