1
PHYS 612
ENDOCRINOLOGY
LECTURE NOTES
BY
Richard F. Laherty, Ph.D.
2000, Richard F. Laherty, Ph.D.
2
TABLE OF CONTENTS
TOPIC
PAGE
1.
Introduction
1
2.
Pituitary Gland and Hypothalamus
5
3.
The Thyroid Gland
16
4.
Endocrine Pancreas
23
5.
Diabetes and Hypoglycemia
29
6.
Hormones of the Gut
33
7.
Hormones Affecting Blood Cell Production
& Function
41
8.
Calcium and Phosphate Homeostasis
46
9.
Adrenal Cortex
51
10. Adrenal Medulla
60
11. Male Reproductive System
67
12. Female Reproductive System
72
13. Pregnancy
80
1
INTRODUCTION
I.
Homeostasis:
A.
II.
III.
Regulatory Systems
1.
Nervous
2.
Endocrine
Definitions:
A.
Endocrine:
B.
Exocrine:
C.
Hormone:
D.
Paracrine:
E.
Autocrine:
Types of Hormones:
A.
Water Soluble (Polar):
1.
Peptides
a)
2.
Proteins
a)
3.
Ex: Growth Hormone (GH)
Amino Acid
a)
B.
Ex: Antidiuretic Hormone (ADH)
Ex: Epinephrine
Lipid Soluble (Non-Polar):
1.
Steroids
PHYS 628
Introduction
a)
2.
Ex: Cortisol
Amino Acid
a)
IV.
Page: 2
Ex: Thyroid Hormone, Thyroxine (T4)
Mechanism of Hormone Action:
A.
B.
Receptors:
1.
Specificity:
2.
Affinity:
3.
Capacity:
Water Soluble Hormones:
1.
Membrane Protein:
2.
Signal Transduction:
a)
3.
(1)
Cyclic-AMP:
(2)
Cyclic-GMP:
(3)
Phosphatidylinositol:
(4)
Calcium-Calmodulin
(5)
Tyrosine Kinase
Up/Down Regulation of Proteins Already Present:
a)
C.
Second Messenger Systems:
Primarily by Phosphorylation/Dephosphorylation
Lipid Soluble Hormones:
1.
Cytosolic/Nuclear Protein:
a)
Up/Down Regulation of Genes
(1)
Stimulate/Inhibit Protein Synthesis
PHYS 628
Introduction
2.
V.
Control of Endocrine Secretion:
A.
B.
VI.
Membrane Receptors:
Negative Feedback
1.
Ex: Thermostat/Heater
2.
Ex: Insulin/Glucose
Positive Feedback
1.
Ex: Dam Breaking
2.
Ovulation
Plasma Concentration of a Hormone:
A.
B.
Secretion:
1.
Tonic vs Episodic
2.
Rhythms
a)
Ultradian
b)
Circadian
c)
Monthly
d)
Seasonal
e)
Developmental
Transport
1.
Polar/Water soluble:
2.
Non-Polar/Lipid Soluble
a)
Transport Proteins
(1)
Ex: Thyroid Binding Globulin
Page: 3
PHYS 628
Introduction
b)
Non-Specific Protein Binding
(1)
c)
C.
D.
Free Hormone Levels
Metabolism
1.
Liver
2.
Other
Excretion
1.
Ex: Albumin
Kidney
Page: 4
5
PITUITARY GLAND AND HYPOTHALAMUS
I.
II.
Anatomical Relations
A.
Sella Turcica
B.
Optic Chiasm
C.
Median Eminence
D.
Mamillary Body
E.
Cavernous Sinus
Subdivisions of the Pituitary (Hypophysis)
A.
B.
III.
Adenohypophysis (Anterior Pituitary)
1.
Pars Distalis
2.
Pars Intermedia
3.
Pars Tuberalis
Neurohypophysis (Posterior Pituitary)
1.
Pars Nervosa
2.
Infundibular Stalk
Adenohypophysis
A.
Pars Distalis
1.
Cells:
a)
Acidophils
(1)
Somatotroph
(a)
Produces Growth Hormone (GH)
PHYS 628
Anterior Pituitary & Hypothalamus
Page 6
Terminology regarding abbreviations:
Hormone name in capital letters, species in lower
case. Ex: human growth hormone (hGH), bovine
growth hormone (bGH)
(2)
Lactotroph
(a)
b)
Basophils
(1)
(2)
Gonadotrophs
(a)
Follicle Stimulating Hormone (FSH)
(b)
Luteinizing Hormone (LH)
Thyrotrophs
(a)
c)
d)
2.
Produces Prolactin (PRL)
Thyroid Stimulating Hormone (TSH)
Corticotrophs
(1)
Very sparsely granulated, and therefore do not stain
intensely with either basic or acid stains.
(2)
Adrenocorticotrophic Hormone (ACTH)
Chromophobes
Hormones
a)
Prolactin/Growth Hormone Family
(1)
Hormones derived from a common ancestral hormone.
(2)
Prolactin
(3)
(a)
Single chain protein (198 amino acids) with 3
disulfide bonds
(b)
Very little glycosylation
Growth Hormone
(a)
Single chain protein (191 amino acids) with 2
disulfide bonds.
PHYS 628
Anterior Pituitary & Hypothalamus
(b)
b)
c)
B.
C.
IV.
Very little glycosylation
Glycoprotein Family
(1)
All two chain peptides,  and . The  chain is
common to all the hormones in this family. The  chain
gives the hormone its specificity.
(2)
All these hormones are heavily glycosylated.
(3)
Thyroid Stimulating Hormone (TSH)
(4)
Gonadotropins:
(a)
Follicle Stimulating Hormone (FSH)
(b)
Luteinizing Hormone (LH)
Pro-opiomelanocortin Family
(1)
Common precursor
(2)
ACTH
(3)
-Lipotropin
(4)
Endorphin
Pars Intermedia
1.
MSH
a)
Pro-opiomelanocortin Family
b)
Alpha
c)
Beta
Pars Tuberalis
Hypothalamus
A.
Hypothalamo-hypophyseal Portal System
1.
Page 7
Superior hypophyseal artery
PHYS 628
B.
V.
VI.
Anterior Pituitary & Hypothalamus
Hypothalamic Releasing Hormones
1.
Thyrotropin Releasing Hormone (TRH)
2.
Corticotropin Releasing Hormone (CRH)
3.
Gonadotropin Releasing Hormone (GnRH)
4.
Growth Hormone Releasing Hormone (GRH
5.
Somatostatin (GIH)
6.
Prolactin Inhibiting Hormone (PIH)
Feedback Control of Anterior Pituitary Hormones
A.
Long Loop
B.
Short Loop
C.
Ultrashort Loop
D.
Amplitude
E.
Frequency
Pathologies
A.
Hypersecretion
B.
Hyposecretion
C.
Classification
D.
1.
Primary
2.
Secondary
3.
Tertiary
Pituitary adenomas
Page 8
PHYS 628
VII.
Anterior Pituitary & Hypothalamus
Page 9
Growth Hormone
A.
B.
Chemistry
1.
Single chain protein, 191 amino acids
2.
MW 21,500
3.
2-disulfide bridges
4.
Synthesized as part of a larger protein, preGH (MW 28,000)
Function
1. Primarily mediated by Insulin-like Growth Factor 1 (IGF-1)
a)
Somatomedin C
b)
Produced primarily by the Liver
2. Increase linear growth
3. Increase protein synthesis
c)
Increase amino acid uptake
d)
Increase transcription and translation
4. Decrease protein catabolism
5. Increase lipid catabolism
6. Decrease carbohydrate uptake and utilization
C.
Control of Secretion:
1.
GRH
a)
40 & 44 amino acid types
b)
cAMP mechanism
c)
Stimulates synthesis & secretion of GH
PHYS 628
Anterior Pituitary & Hypothalamus
2.
3.
4.
D.
Somatostatin
a)
Tetradecapeptide
b)
Decreases cAMP
c)
Inhibits synthesis & secretion of GH
Neural regulation
a)
Sleep stimulates GH secretion
b)
Stress stimulates GH secretion
Metabolic control
a)
Amino acids stimulate
b)
Glucose inhibits
c)
Lipids inhibit
Pathologies
1.
2.
Hypersecretion
a)
Gigantism
b)
Acromegaly
c)
Glucose intolerance
Hyposecretion
a)
Dwarfism
VIII. Prolactin (PRL)
A.
Chemistry
1.
Single chain protein, 198 amino acids
2.
3 disulfide bridges
Page 10
PHYS 628
B.
C.
IX.
Anterior Pituitary & Hypothalamus
Function:
1.
Stimulates lactation
2.
Other
Control of Secretion
1.
PIH (Dopamine)
2.
TRH
3.
Sleep
4.
Stress
Adrenocorticotropic Hormone (ACTH)
A.
Chemistry
1.
B.
Peptide, 39 amino acids, MW=4,500
Biosynthesis
1.
Pro-opiomelanocortin (POMC)
a)
b)
c)
C.
ACTH
(1)
-MSH
(2)
CLIP
-Lipotropin (LPH)
(1)
-MSH
(2)
-Endorphin
Amino Terminal Fragment (131 amino acids)
Function
1.
Stimulate secretion of adrenal steroids, particularly
glucocorticoid
Page 11
PHYS 628
Anterior Pituitary & Hypothalamus
2.
D.
Control of Secretion
1.
X.
Trophic effect
CRH
Thyroid Stimulating Hormone (TSH)
A.
Chemistry
1.
Glycoprotein
2.
2 protein chains
a)
-subunit
(1)
b)
-subunit
(1)
B.
C.
XI.
Common to all glycoprotein hormones
Specific activity
Function
1.
Stimulate thyroid hormone production and synthesis
2.
Trophic effect
Control
1.
TRH
2.
Somatostatin
Gonadotropins
A.
Follicle Stimulating Hormone (FSH)
B.
Luteinizing Hormone (LH)
C.
Chemistry
1.
Glycoprotein
Page 12
PHYS 628
Anterior Pituitary & Hypothalamus
2.
2 protein chains
a)
-subunit
(1)
b)
Stimulate function of the gonads
Control
1.
XII.
Specific activity
Function
1.
E.
Common to all glycoprotein hormones
-subunit
(1)
D.
Page 13
GnRH
Posterior Pituitary (Pars Nervosa)
A.
Anatomical Structure
1.
B.
An extension of the hypothalamus
a)
Supraoptic nucleus
b)
Paraventricular nucleus
2.
Pituicytes
3.
Axons
Hormones
1.
Antidiuretic Hormone (ADH, Vasopressin)
a)
Primarily from the supraoptic nucleus
b)
Chemistry
c)
(1)
Nonapeptide, with ring structure, disulfide bridge
(2)
Synthesized as part of a larger molecule, neurophysin-II
Receptors
PHYS 628
Anterior Pituitary & Hypothalamus
(1)
(2)
d)
e)
f)
2.
Page 14
V1
(a)
Vascular smooth muscle
(b)
Phosphatidylinositol pathway
V2
(a)
Kidney
(b)
cAMP pathway
Function:
(1)
Vasoconstriction, increased blood pressure.
(2)
Increased water reabsorption by kidney
Control:
(1)
Plasma osmolality
(2)
Blood pressure
Diabetes insipidus
Oxytocin (Pitocin)
a)
Primarily from the paraventricular nucleus
b)
Chemistry
c)
(1)
Nonapeptide, with ring structure, disulfide bridge
(2)
Synthesized as part of a larger molecule, neurophysin-I
Receptors
(1)
d)
Phosphatidylinositol pathway
Function
(1)
Increases frequency and duration of uterine smooth
muscle contraction
PHYS 628
Anterior Pituitary & Hypothalamus
(2)
Page 15
(a)
Estrogen causes uterine smooth muscles cells to
become slightly depolarized.
(b)
Parturition: positive feedback
Stimulates milk “let down.”
(a)
Acts on myoepithelial cells of the mammary
gland
(b)
Neuroendocrine reflex: suckling reflex.
16
THE THYROID GLAND
I.
Anatomical Structure
A.
Gross Anatomy
1.
Located in neck
a)
Anterior surface of the trachea
b)
Two lobes connected by isthmus
(1)
2.
3.
4.
B.
Pyramidal lobe
Relations
a)
Larynx
b)
Trachea
c)
Recurrent laryngeal nerve
d)
Parathyroid glands
e)
Carotid sheath
Blood supply
a)
Superior thyroidal arteries
b)
Inferior thyroidal arteries
Embryology
a)
Thyroglossal duct
b)
Foramen caecum
c)
Thyroid cysts
Histology
PHYS 628
The Thyroid Gland
1.
Thyroid follicles
a)
b)
Simple cuboidal-columnar
(1)
Height of epithelium related to activity of the gland
(2)
Well developed RER
(3)
Well developed Golgi
(4)
Contain numerous lysosomes
(5)
Extensive development of microvilli on the luminal
surface
Colloid
(1)
Thyroglobulin
(a)
(b)
Glycoprotein
(i)
5,496 amino acids
(ii)
MW: 660,000
Rich in tyrosine residues
(i)
c)
2.
II.
Page 17
140/molecule
Rich vascularization surrounding each follicle
Parafollicular cells
a)
Found between follicles
b)
Different embryonic origin
Thyroid Hormone
A.
Modified amino acids with iodine attached
B.
3-Monoiodotyrosine (MIT)
C.
3,5-Diiodotyrosine (DIT)
D.
3,3’,5-Triiodothyronine (T3)
PHYS 628
III.
IV.
V.
The Thyroid Gland
E.
3,3’,5,5’-Tetraiodothyronine (T4)
F.
Reverse T3: 3,3’,5’-Triiodothyronine
Thyroid Hormone Biosynthesis
A.
Iodine pump/trap
B.
Thyroglobulin synthesis and secretion
C.
Iodination of tyrosine residues
1.
Thyroperoxidase
2.
In follicle lumen
D.
Formation of thyronine
E.
Pinocytosis of thyroglobulin
F.
Release of thyroid hormone
Thyroid hormone transport
A.
Thyroid binding globulin (TBG)
B.
Thyroid binding prealbumin
C.
Albumin
Thyroid hormone action
A.
5’-deiodinase
1.
T3 is 3-8X more active than T4
2.
T4 probably a pro-hormone
B.
Thyroid hormone receptor
C.
Physiological effects of thyroid hormone
1.
Increases oxygen consumption and heat production
Page 18
PHYS 628
The Thyroid Gland
2.
Positive chronotropic and inotropic effects on heart
3.
Increase sensitivity to adrenergic effectors
a)
VI.
Up-regulates -adrenergic receptors
4.
Increase gut motility
5.
Increase bone turnover
6.
Increases reflex response
7.
Increase hepatic glycogenolysis and gluconeogenesis
8.
Stimulates lipolysis
9.
Developmental effects
a)
Growth
b)
Brain development
Regulation of thyroid hormone
A.
Hypothalamo-pituitary-thyroid axis
1.
Thyroid Releasing Hormone (TRH)
a)
Tripeptide
b)
Effect of TRH on thyrotrope
(1)
c)
Long-loop feedback
(1)
2.
Estrogen effects
T4 more important
Thyroid Stimulating Hormone (TSH)
a)
Effect on thyroid follicle cell
(1)
Increase size (height) of cell
(2)
Stimulates thyroglobulin reabsorption
Page 19
PHYS 628
The Thyroid Gland
b)
VII.
(3)
Increase iodine transport and attachment to tyrosine
residues
(4)
Increase thyroglobulin synthesis
(5)
Increase thyroperoxidase synthesis
(6)
Increase lysosomal activity
Thyroid hormone feedback
3.
Autoregulation of the thyroid
4.
TSH-receptor autoantibodies
5.
Neuroendocrine effects
6.
Exposure to cold
7.
Effect of serum iodine levels
8.
Goitrogens
a)
Propylthiouracil
Endocrinopathies
A.
Page 20
Hyperthyroidism
1.
Level of the defect (primary, secondary, tertiary)
2.
Thyrotoxicosis
3.
Graves’ disease
a)
Autoimmune disease
b)
Palpitations
c)
Nervousness
d)
Excessive sweating/intolerance to heat
e)
Hyperkinesia
PHYS 628
The Thyroid Gland
f)
Diarrhea
g)
Exophthalmos
h)
Accelerated growth and bone maturation in
children
i)
Thyroid enlargement
(1)
B.
Goiter
j)
Muscle weakness/loss of muscle mass
k)
Weight loss
l)
Tachycardia
4.
Toxic Adenoma
5.
Toxic Multinodular Goiter
6.
Chronic Thyroiditis
Hypothyroidism
1.
Primary, Secondary, or Tertiary
2.
Newborn
a)
3.
4.
Cretinism
(1)
Dwarf
(2)
Mental retardation
Children
a)
Retarded growth
b)
Mental deficiency
Adult
a)
Muscle weakness
Page 21
PHYS 628
The Thyroid Gland
(1)
Including heart
(2)
Bradycardia
(3)
Slow respirations
b)
Tired/fatigued
c)
Cold
d)
Slowed intestinal peristalsis
e)
Impaired renal function
f)
anemia
g)
Myxedema
C.
Thyroid hormone resistance
D.
Non-toxic goiter
1.
E.
Iodine deficiency
Thyroiditis
1.
Subacute thyroiditis
2.
Chronic thyroiditis (Hashimoto’s Disease)
a)
Autoimmune
VIII. Allopathic treatments for thyroid disorders
A.
B.
Hyperthyroidism
1.
Goitrogens
2.
Partial thyroidectomy
3.
Radiothyroidectomy
Hypothyroidism
Page 22
23
ENDOCRINE PANCREAS
I.
Anatomy
A.
Location
1.
B.
Pancreatic Islets (of Langerhans)
1.
2.
3.
4.
II.
Scattered throughout the pancreas
Alpha cells (15-20% of Islet cells)
a)
Center of Islet
b)
Produce and secrete Glucagon
Beta cells (70-80% Islet cells)
a)
Periphery of Islet
b)
Produce and secrete Insulin
Delta cells (3-5% Islet cells)
a)
Throughout Islet
b)
Produce and secrete somatostatin
F-cells (2-4% Islet cells)
a)
Few in number
b)
Produce and secrete pancreatic peptide
Hormones
A.
Insulin
1.
Chemistry
a)
Protein/Peptide
PHYS 628
The Endocrine Pancreas
b)
(1)
51 amino acids
(2)
2-chains
(a)
 &
(b)
2 disulfide bridges
Proinsulin
(1)
86 amino acid protein contain insulin
(2)
C peptide
(3)
(a)
31 amino acid connecting peptide
(b)
released with insulin
Converted to insulin by 2 peptidases
(a)
2.
Cleave hormone at 2 sites, releasing 4 amino
acids
Action
a)
b)
Page 24
Insulin Receptor
(1)
Kinase on the cytoplasmic side of the receptor
(2)
Autophosphorylation of the receptor
(3)
Phosphorylation of neighboring proteins
(4)
Translocation of GLUT-4
(5)
Down-regulation of insulin receptor
Glucose Transporter Proteins
(1)
(2)
GLUT-1
(a)
Brain vessels
(b)
Very high affinity
GLUT-2
PHYS 628
The Endocrine Pancreas
(3)
(4)
(5)
c)
d)
(a)
Liver and Islet -cell
(b)
Low affinity
Page 25
GLUT-3
(a)
Brain neurons
(b)
Very high affinity
GLUT-4
(a)
Muscle & fat cells
(b)
Medium affinity
(c)
Upregulated by insulin
GLUT-5
(a)
Jejunum, Liver, & sperm
(b)
Primarily a fructose transporter
(c)
Medium affinity
Basic effect of Insulin
(1)
Promotes uptake of glucose from the blood
(2)
Promotes storage of energy-producing nutrients
Effect of Insulin on the Liver
(1)
Stimulates glycogenesis
(2)
Stimulates protein synthesis
(3)
Increased production of triglycerides, cholesterol, and
VLDL
(4)
Inhibits glycogenolysis
(5)
Inhibits ketogenesis
(6)
Inhibits gluconeogenesis
PHYS 628
The Endocrine Pancreas
e)
f)
Effect of Insulin on Skeletal Muscle
(1)
Promotes protein synthesis
(2)
Stimulates glycogen synthesis
Effect of Insulin on Fat Cells
(1)
3.
Regulation
a)
b)
B.
Promotes triglyceride storage
Factors that stimulate insulin secretion
(1)
High serum glucose
(2)
High serum amino acids
(3)
Enteric hormones
(a)
Gastrin
(b)
Secretin
(c)
Secretin
Factors that inhibit insulin secretion
(1)
Glucagon
(2)
-adrenergic stimulation
Glucagon
1.
2.
Chemistry
a)
29 amino acid peptide
b)
Proglucagon
Action
a)
Antagonizes the action of insulin
b)
Acts primarily on the liver
Page 26
PHYS 628
The Endocrine Pancreas
3.
c)
Stimulates glycogenolysis
d)
Stimulates gluconeogenesis
e)
Stimulates ketogenesis
Regulation
a)
Serum glucose
(1)
b)
Hypoglycemia stimulates glucagon
Somatostatin
(1)
C.
Inhibits glucagon
c)
Sympathetic and parasympathetic stimulation
both increase glucagon release
d)
G-I hormones stimulate glucagon release
e)
Glucocorticoids stimulate glucagon release
Somatostatin
1.
2.
Page 27
Chemistry
a)
14 amino acid peptide
b)
Prosomatostatin
c)
G-protein linked receptor
d)
Produced and secreted by many tissues
(1)
CNS
(2)
Pancreas
(3)
G-I tract
Action
a)
Action in the pancreas primarily paracrine
PHYS 628
The Endocrine Pancreas
3.
b)
Inhibits insulin secretion
c)
Also inhibits glucagon secretion
Regulation
a)
D.
Page 28
Stimulators of insulin release also stimulate
somatostatin release
Pancreatic Peptide
1.
Chemistry
a)
2.
Action
a)
3.
36 amino acid peptide
unknown
Regulation
a)
Serum levels increase after a meal, but do not
increase after glucose infusion
b)
Vagotomy abolishes response to meal
29
DIABETES AND HYPOGLYCEMIA
I.
What is Diabetes Mellitus?
A.
“Starvation in a sea of plenty.”
B.
Hyperglycemia
1.
Polyuria
a)
Osmotic diuresis
(1)
C.
Polydipsia
1.
D.
II.
Serum glucose > 200 mg/dl
Compensation for diuresis
Ketosis
1.
Ketonuria
2.
Acetone breath
E.
Acidosis
F.
Coma
Types of Diabetes Mellitus
A.
Type I
1.
Lack of -cells in the pancreatic islet
2.
Little or no insulin production
3.
Usually occurs during childhood/adolescence
a)
4.
Once known as juvenile diabetes
Autoimmune disease
PHYS 628
B.
Diabetes Mellitus & Hypoglycemia
a)
Possibly triggered by infection
b)
Genetic predisposition
Type II
1.
Insulin resistance
2.
Usually occurs during adult life
a)
C.
III.
Once known as adult onset diabetes
3.
Strong genetic predisposition
4.
Environmental factors
a)
Obesity
b)
Lack of exercise
Gestational diabetes
Effects of Uncontrolled Diabetes Mellitus on the Body
A.
Primary effect of Insulin deficiency
1.
Hyperglycemia
2.
Polyuria
3.
Polydipsia
4.
Ketosis
a)
Due to shift to lipid catabolism
5.
Ketonuria
6.
Acidosis
7.
Coma
8.
Death
Page 30
PHYS 628
B.
Aberrant glucagon secretion
C.
Diabetic vascular disease
D.
IV.
Diabetes Mellitus & Hypoglycemia
1.
Microvascular changes
2.
Macrovascular changes
Secondary effects of insulin deficiency
1.
Retinopathy
2.
Peripheral neuropathy
3.
Renal disease
4.
Cardiovascular disease
5.
Wound healing/Infection
6.
Skin disease
7.
Bone and joint complications
Monitoring and diagnosing diabetes mellitus
A.
Blood glucose levels
1.
B.
Glucose tolerance test
C.
Glycosylated hemoglobin
1.
V.
Fasting: 80-120 mg/dl
HbA1C
Treatments for Diabetes Mellitus
A.
Type I
1.
Insulin
2.
Diet
Page 31
PHYS 628
B.
VI.
Diabetes Mellitus & Hypoglycemia
3.
Exercise
4.
Support
Type II
1.
Diet & exercise
2.
Oral hypoglycemic drugs
3.
Insulin
4.
Reversing insulin resistance
5.
Support
Hypoglycemia
A.
B.
C.
D.
What is hypoglycemia?
1.
Blood sugar below 40 mg/dl
2.
Loss of consciousness
What causes hypoglycemia?
1.
Hyperinsulinism
2.
Overdoes of anti-diabetic drugs
3.
Exercise in diabetics
Treatment
1.
Timing of eating
2.
Diet
Relationship of hypoglycemia to type-II diabetes
Page 32
33
Hormones of the Gut
I.
Beginning of Endocrinology
A.
B.
II.
Bayliss and Starling--1902
1.
Acidification of denervated duodenum or jejunum stimulated
pancreatic exocrine secretion.
2.
Injected extract of jejunal mucosa also stimulated pancreatic
exocrine secretion.
3.
Postulated a humoral regulatory factor they called “Secretin.”
Secretin finally isolated in 1961.
Gut Regulatory Peptides
A.
Gut Nervous System
B.
Endocrine cells of mucosa
1.
C.
Basal secretory granules
Gut Peptides may be
1.
Hormones
a)
Travel to different organ through blood stream.
2.
Paracrine
3.
Neurosecretory
4.
Neurotransmitters
PHYS 628
III.
Calcium & Phosphate Homeostasis
Secretin
A.
29 amino acid peptide
1.
B.
C.
Related to: glucagon, GIP, VIP, PHI, PHM (Secretin family)
Action:
1.
IV.
Page 34
Stimulates Bicarbonate and Water Secretion by Pancreas
Secretin Control
Gastrin
A.
1905, Edkins discovered that an extract of gastric mucosa
stimulated acid secretion that he called Gastrin.
B.
1960s, Gregory isolated and sequenced Gastrin.
C.
3 biologically active forms:
1.
“Big” = 34 amino acids
2.
‘Little” = 17 amino acids
3.
“Mini” = 14 amino acids
4.
Structurally similar to Cholecystokinin:
a)
D.
Gastrin-Cholecystokinin Family.
Found in endocrine cells of gastric antrum.
1.
Also identified in CNS.
PHYS 628
E.
F.
Calcium & Phosphate Homeostasis
Stimulated by proteins and amino acids in gastric lumen.
1.
Carbohydrates and Fats in effective.
2.
Somatostatin inhibits Gastrin release
Gastrin Action
1.
Stimulates Acid Secretion by Gastric Mucosa
a)
G.
V.
Page 35
May be due to stimulation of histamine release by
neighboring cells (paracrine)
2.
Stimulates growth of parietal cells of the Gastric Mucosa
3.
Stimulates Mucosal blood flow
4.
Stimulates Pepsin Release
Gastrin Control
Cholecystokinin (CCK)
A.
History
1.
1928: Fat in small intestine stimulates the gall bladder to
contract--cholecystokinin.
2.
1940s: Extract of duodenal mucosa stimulates pancreas to
secrete enzymes--pancreozymin.
3.
1964-8: Purification of a single substance that stimulated
both contraction of the gall bladder and pancreatic enzyme
secretion--settled on one name: cholecystokinin (CCK).
PHYS 628
B.
C.
D.
E.
Calcium & Phosphate Homeostasis
Page 36
Structure
1.
Polypeptide found in different forms including: 58, 39, 33, &
8 amino acids.
2.
8 amino acid form has full biological potency.
3.
Carboxy terminal 8 amino acids identical in all forms.
4.
Larger forms may be prohormones.
5.
Preprocholecystokinin found: 115 amino acids.
Cholecystokinin Location:
1.
Located in duodenal and proximal jejunal mucosa.
2.
Also found in CNS.
CCK Secretion Stimulated
1.
By the presence of intraduodenal protein or fat.
2.
May be a low molecular weight
CCK-releasing factor.
3.
Release is inhibited by somatostatin.
CCK Actions
1.
Stimulates contraction of gall bladder, forcing bile into the
duodenum.
2.
Stimulates pancreatic enzyme secretion.
PHYS 628
F.
VI.
Calcium & Phosphate Homeostasis
3.
Trophic effects on pancreatic acini.
4.
Causes sphincter of Oddi to relax.
5.
Induces satiety.
Page 37
CCK Control
Somatostatin
A.
14 & 28 amino acid forms.
B.
Found in hypothalamus, throughout CNS and Gut (including
pancreas)
C.
Major inhibitory peptide of Gut. Inhibits secretion of
D.
1.
insulin
2.
glucagon
3.
CCK
4.
secretin
5.
gastrin
6.
VIP
7.
somatostatin (autocrine)
Somatostatin Control
PHYS 628
VII.
Calcium & Phosphate Homeostasis
Other Peptides
A.
B.
C.
Vasoactive Intestinal Peptide (VIP)
1.
Neurotransmitter/neuroendocrine
2.
Relax esophageal and anal sphincter
3.
Increases blood flow in the gut
4.
Causes penile erection
Gastrin-Releasing Peptide (GRP)
1.
Neurotransmitter/neuroendocrine
2.
Stimulates release of Gastrin
Substance P
1.
Neurotransmitter
2.
Stimulates Contraction of Smooth Muscle
D.
Enkephalins
E.
Neurotransmitter
F.
Inhibits gut motility, antagonizes action of Substance P
VIII. ENERGY RESERVES AND METABOLISM
A.
TWO TYPES OF NEURONS
1.
INCREASE/DECREASE METABOLISM
Page 38
PHYS 628
Calcium & Phosphate Homeostasis
2.
OREXIGENIC/ANOREXIGENIC NEURONS
3.
MELANOCORTIN
a)
αMSH
(1)
4.
POMC
b)
INHIBITS FEEDING BEHAVIOR
c)
INCREASES METABOLISM
NEUROPEPTIDE-Y (NPY)
a)
AGOUTI-RELATED PEPTIDE (AgRP)
(1)
B.
Page 39
COMPETITIVE INHIBITOR OF
MELANOCORTIN RECEPTORS
b)
STIMULATES FEEDING BEHAVIOR
c)
DECREASES METABOLISM
d)
INHIBITS MELANOCORTIN NEURONS
RECEPTORS FOR PERIPHERAL SIGNALS
1.
ENERGY BALANCE INDICATORS
a)
b)
LONG-TERM ENERGY STORES (ADIPOSE)
(1)
LEPTIN
(2)
INSULIN
SHORT-TERM ENERGY STORES (SATIETY)
(1)
GHRELIN
(2)
PEPTIDE YY
PHYS 628
Calcium & Phosphate Homeostasis
(3)
CHOLECYSTOKININ (CCK)
Page 40
41
Hormones Affecting Blood Cell Production &
Function
I.
II.
Hormones
A.
Erythropoietin
B.
Leukopoietin
C.
Thymosin
Erythropoietin
A.
Structure
1.
B.
Produced primarily by peritubular capillary endothelial cells
(Kidney)
1.
C.
D.
165 amino acid glycoprotein, MW = 30,000
Minor production by Liver
Receptor with a single transmembrane domain
1.
Requires dimerization like PRL/GH receptor
2.
Binds to and activates JAK-2
Erythropoietin Action
1.
In concert with other growth factors
a)
Stimulates growth and maturation of erythroblast
line
PHYS 628
E.
III.
IV.
A.
Calcium & Phosphate Homeostasis
b)
Stimulates growth of megakaryocyte
c)
Stimulates the initiation of megakaryocyte
process formation
Page 42
Erythropoietin Control
Leukopoietin
A.
Postulated to Exist
B.
Stimulate production of Myeloid cells.
Thymic Hormones
History
B.
1.
Thymic ablation in adult animals had no observable effect.
2.
Neonatal Thymectomy
a)
Wasting Disease
b)
Death from opportunistic infections
3.
Wasting Disease also after radiation & thymectomy.
4.
Wasting Disease prevented by thymic extracts--Thymosin
Thymosins
1.
Thymosin Fraction 5:
a)
Crude preparation of 40-60 peptides
PHYS 628
Calcium & Phosphate Homeostasis
2.
3.
Page 43
b)
Enhances natural killer cell (NK-cell) activity.
c)
Stimulates secretion of Interleukin-2 (IL2)
production
d)
Stimulates IL2 receptor expression
e)
Stimulates IL1 and tumor necrosis factor (TNF)
production
Thymosin-alpha-1
a)
28 amino acid peptide
b)
113 amino acid prohormone, prothymosin alpha
c)
Induces differentiation of T-cell precursors
d)
Stimulates production of IL2, IL2 receptor & B-cell
growth factor
e)
Helper (CD4+) and cytotoxic (CD8+) T-cells are
target
f)
Increases efficiency of antigen presentation by
antigen presenting cells
g)
Paracrine/autocrine factor
h)
Regulation not known
Beta-thymosins
a)
Group of related proteins who’s effect on
lymphocytes is poorly understood
PHYS 628
C.
Calcium & Phosphate Homeostasis
b)
May be induced by interferon
c)
Thymosin-Beta-4 acts on differentiation and
maturation of early T-cells
d)
Many of the beta-thymosins are expressed by
tumor cells and may be involved in metastasis.
Other Thymic Peptides
1.
2.
3.
Page 44
Thymostimulin (TP-1)
a)
Enhanced production of IL2 and interferon
b)
Reduces postoperative infection rates of
immunocompromised patients
Thymopoietin
a)
Stimulates differentiation of T-cells while
inhibiting differentiation of B-cells
b)
Increased IL2 and IL2 receptor expression
c)
Increased size of T-cell pool
d)
Increased NK-cell activity.
Thymulin (Serum thymic factor)
a)
Increases T-cell populations probably via
stimulation of IL1
b)
Production stimulated by PRL & GH
PHYS 628
D.
Calcium & Phosphate Homeostasis
Page 45
AIDS
1.
Thymic peptides have been used to enhance the immune
system of HIV infected individuals.
46
CALCIUM AND PHOSPHATE HOMEOSTASIS
I.
Organs:
A.
Parathyroid
1.
Four oval masses embedded on the posterior of the thyroid
gland
2.
Derived embryonically from the 3rd and 4th pharyngeal
pouches
3.
Cell Types
4.
a)
Chief
b)
Oxyphil
Parathyroid hormone (PTH)
a)
b)
Protein/peptide
(1)
84 amino acids
(2)
Prepro-PTH
Metabolized in liver and kidney
(1)
c)
B.
Biological half-life: 2-4 minutes
Receptor: G protein associated receptor
(1)
Gs & Gq both associated with receptor
(2)
Believe cAMP is primary second messenger for Ca++
homeostasis.
Thyroid (Parafollicular cells)
1.
Cells located outside the thyroid follicles
2.
Derived embryonically from the ultimobranchial body
PHYS 628
Calcium & Phosphate Homeostasis
3.
Make up about 0.1% of the mass of the thyroid
4.
Calcitonin
a)
32-amino acid peptide
b)
Acts through serpentine receptor
(1)
C.
cAMP is the second messenger
Vitamin D
1.
Sterol hormone
2.
Production of the active hormone requires several organs
3.
Production:
a)
7-dehydrocholesterol
b)
Cholecalciferol (Vitamin D3) in skin
(1)
c)
d)
4.
In liver
1,25-Dihydroxy Cholecalciferol (1,25-Dihydroxy
Vitamin D3)
(1)
e)
Requires UV light
25 Hydroxy Cholecalciferol (25-hydroxy vitamin
D3)
(1)
II.
In kidney
No dietary source of Vitamin D3
(1)
Use Vitamin D
(2)
, from ergosterol.
Binds to an intracellular receptor
Actions of the Hormones
A.
Page 47
Parathyroid hormone (PTH)
PHYS 628
Calcium & Phosphate Homeostasis
1.
Increases serum Ca++ concentration
2.
Kidney
3.
4.
B.
a)
Increase Ca++ reabsorption
b)
Decrease phosphate reabsorption
Page 48
Bone
a)
Activates osteoclasts
b)
Reabsorb mineral (Ca++ & phosphate)
Intestine
a)
Indirect action due to direct action of increasing
level of vitamin D3
b)
Increase intestinal absorption of Ca++
Calcitonin
1.
Decreases serum Ca++ concentration
2.
Bone
a)
3.
4.
5.
Decreases activity of osteoclasts
Kidney
a)
Decreases Ca++ reabsorption
b)
Decreases phosphate reabsorption
Question of its physiological role
a)
Thyroidectomy has no demonstrable effect on
mineral metabolism
b)
Hypersecretion of calcitonin by medullary thyroid
carcinoma has no apparent effect on mineral
homeostasis
Clinical usefulness
PHYS 628
C.
III.
Calcium & Phosphate Homeostasis
Marker for medullary thyroid carcinoma
b)
Treatment of osteoporosis/osteomalacia
Dihydroxy-Vitamin D
1.
Increases intestinal absorption of Ca++
2.
Stimulate bone matrix protein production by osteoblasts
3.
Activate osteoclasts
4.
Increase phosphate reabsorption by kidney
5.
Maintain Ca++ reabsorption by the kidney
Regulation of secretion:
A.
Parathyroid hormone and Calcitonin
1.
B.
Serum Ca++ levels
Vitamin D
1.
IV.
a)
Sunlight exposure
Pathologies
A.
Hypercalcemia
1.
B.
Hyperparathyroidism
Hypocalcemia
1.
C.
Page 49
Hypoparathyroidism
a)
Surgical
b)
Idiopathic
Osteoporosis
1.
Role of estrogen
PHYS 628
Calcium & Phosphate Homeostasis
D.
Paget’s Disease
E.
Osteomalacia
Page 50
51
ADRENAL CORTEX
I.
II.
Introduction
A.
Adrenal Location
B.
Adrenal Cortex
C.
Adrenal Medulla/Chromaffin Tissue
D.
Different embryological origins
E.
Not together below birds
Adrenal Morphology
A.
Embryology
1.
B.
C.
III.
Intermediate mesoderm
Zones
1.
Zona Glomerulosa
2.
Zona Fasciculata
3.
Zona Reticularis
Cytology
1.
Extensive lipid inclusions
2.
Extensive SER
3.
Mitochondria with tubular cristae
Adrenal Steroid Pathways
A.
Cholesterol
PHYS 628
Adrenal Cortex
1.
2.
Source
a)
Low Density Lipoproteins (LDL)
b)
De Novo Synthesis
Side Chain Cleavage Enzyme
a)
B.
Cytochrome p450
Pregnenolone
1.
Progesterone
a)
3-hydroxysteroid dehydrogenase-isomerase
52
PHYS 628
Adrenal Cortex
b)
53
11-deoxycorticosterone
(1)
21-hydroxylase
(2)
Corticosterone
(a)
11-hydroxylase
(i)
Aldosterone
(a)
c)
17-hydroxyprogesterone
(a)
17-hydroxylase
(b)
11-dexoycortisol
(i)
21-hydroxylase
(ii)
Cortisol
(a)
2.
11-hydroxylase
17-hydroxypregnenolone
a)
17-hydroxylase
b)
dehydroepiandrosterone
(1)
3.
18-hydroxylase & 18hydroxysteroid dehydrogenase
C17-20 Lyase
Androstenedione
a)
From
(1)
dehydroepiandrosterone
(a)
(2)
17-hydroxyprogesterone
(a)
b)
3-hydroxysteroid dehydrogenase-isomerase
C17-20 Lyase
Testosterone
PHYS 628
Adrenal Cortex
(1)
17-hydroxysteroid dehydrogenase
(2)
Estradiol
(a)
c)
Estrone
(1)
Aromatase
(2)
Estradiol
(a)
IV.
Aromatase
17-hydroxysteroid dehydrogenase
Mineralocorticoids
A.
Primarily produced by zona glomerulosa
B.
Principal mineralocorticoid is aldosterone
C.
Aldosterone actions
1.
Promote Na+ reabsorption
2.
Inhibit K+ reabsorption
54
PHYS 628
D.
Adrenal Cortex
3.
Antidiuretic
4.
Acts primarily on the proximal convoluted tubule
Regulation of aldosterone secretion
1.
Serum Na+ and K+
2.
Renin-Angiotensin Pathway
3.
a)
Low blood pressure
b)
Renin secretion by juxtaglomerular apparatus
c)
Renin converts angiotensinogen to angiotensin-I
d)
Angiotensin-I converted to angiotensin-II in Lungs
e)
Angiotensin-II stimulates secretion of aldosterone
f)
Angiotensin-II converted to angiotensin-III
ACTH
a)
E.
55
CRH
Atrial Natriuretic Hormone
1.
28 amino acid peptide
2.
Similar peptides produced in other organs
3.
a)
Brain
b)
Kidney
Actions
a)
cGMP is second messenger
b)
Increases GFR
(1)
Dilation of Afferent arteriole
(2)
Constriction of Efferent arteriole
PHYS 628
Adrenal Cortex
c)
4.
Regulation of secretion
a)
V.
Inhibits Na+ and water reabsorption
Atrial stretch receptors
Glucocorticoids
A.
B.
Which ones are glucocorticoids? (17-hydroxy-)
1.
Cortisol
2.
11-deoxycorticosterone
3.
17-hydroxyprogesterone
4.
17-hydroxypregnenolone
Serum binding proteins
1.
C.
Corticosteroid binding globulin (CBG)
Actions of the Glucocorticoids
1.
Anti-Inflammatory
a)
2.
3.
Inhibits phospholipase-A2
Intermediary Metabolism
a)
Stimulates gluconeogenesis and release of
glucose into the blood.
b)
Protein catabolic, primarily by inhibiting
anabolism.
c)
Decrease glucose catabolism by muscle and
adipose.
d)
Increase lipolysis in adipose tissue.
e)
Inhibit DNA synthesis.
Connective Tissues
56
PHYS 628
Adrenal Cortex
4.
5.
a)
Inhibit collagen formation
b)
Decreased bone deposition
Blood
a)
Increased intravascular levels of neutrophils
b)
Decreased intravascular levels of lymphocytes,
monocytes, & eosinophils
c)
Diminished immune response
Cardiovascular
a)
(1)
Increased cardiac output
(2)
Increased vascular tone
6.
Effects on CNS
7.
Other hormones
8.
D.
Increase blood pressure
a)
Inhibit TSH production
b)
Inhibit GnRH production
Ulcer formation
Control of glucocorticoid secretion
1.
ACTH
a)
2.
Activates side-chain cleavage enzyme
CRH
a)
Feedback effectors
b)
Stress
(1)
General Adaptation Syndrome
57
PHYS 628
Adrenal Cortex
c)
E.
Adrenal androgens
1.
Dehydroepiandrosterone (DHEA)
a)
2.
VI.
Circadian rhythm
DHEA-S
Androstenedione
Pathologies of the Adrenal Cortex
A.
Adrenocortical Insufficiency (Addison’s Disease)
1.
B.
Signs & symptoms
a)
Weakness
b)
Anorexia
c)
Fatigue
d)
Weight loss
e)
Hyperpigmentation (primary only)
f)
Hypotension
g)
G-I disturbances
h)
Salt craving
2.
Crisis
3.
Treatment
Hypersecretion (Cushing’s Disease)
1.
Primary, secondary, or tertiary
2.
Ectopic ACTH production
3.
Signs and symptoms
58
PHYS 628
Adrenal Cortex
4.
C.
a)
Obesity
b)
Thinning of the skin
c)
Striae
d)
Hirsutism
e)
Hypertension
f)
Neuropsychiatric disorders
g)
Weakness
h)
Gonadal dysfunction
i)
Glucose intolerance
Treatment
Androgenital syndrome
59
60
ADRENAL MEDULLA
I.
II.
Anatomy
A.
Deep to the adrenal cortex
B.
Chromaffin cells/tissue
1.
Chromaffin reaction
2.
Neural crest derivative
3.
Produce catecholamines
4.
Highly modified sympathetic ganglion
Hormones
A.
Epinephrine (adrenaline) and Norepinephrine (noradrenaline)
B.
Biosynthesis of Catecholamines
1.
Tyrosine
2.
Dihydroxyphenylalanine (DOPA)
3.
Dopamine
4.
Norepinephrine
5.
Epinephrine
ANAT 628
III.
Adrenal Medulla
Regulation of Adrenal Medullary Secretion
A.
Preganglionic sympathetic innervation
B.
Cholinergic fibers
C.
Modified sympathetic ganglion
D.
Secretes primarily epinephrine
61
ANAT 628
Adrenal Medulla
1.
Effect of adrenal’s vascular supply
2.
All arteries are to the cortex
3.
All veins are in the medulla
4.
Blood supplying the medulla has first passed through the
cortex.
5.
Glucocorticoids increase the activity of PNMT
a)
IV.
Enzyme that catalyzes the conversion of
norepinephrine to epinephrine
Adrenergic receptors
A.
Family of receptors
B.
Alpha () receptors
1.
1
a)
2.
2
a)
3.
DAG/IP3
cAMP
Tissues
a)
Vessels
(1)
Other than skeletal muscle and coronary
b)
GI-tract
c)
Urinary bladder
d)
Uterus
e)
Skin
f)
Pancreas
62
ANAT 628
Adrenal Medulla
g)
C.
Beta () receptors
1.
2.
V.
Dilator pupillae muscle
1
a)
cAMP
b)
Tissues
(1)
Heart
(2)
Kidney
2
a)
cAMP
b)
Tissues
(1)
Liver
(2)
Adipose tissue
(3)
Skeletal muscle
(4)
Arteries of skeletal muscle and coronary arteries
(5)
Bronchial smooth muscle
(6)
GI-tract
(7)
Urinary Bladder
(8)
Uterus
(9)
Erectile tissue
(10)
Ciliary muscle
Actions of Catecholamines
A.
Liver
1.
Stimulates glycogenolysis
63
ANAT 628
B.
Adrenal Medulla
2.
Stimulates gluconeogenesis
3.
Stimulates release of glucose into the blood
Skeletal Muscle
1.
Stimulates glycogenolysis
2.
Stimulates lactate production
a)
C.
D.
E.
Converted to glucose by liver
Adipose Tissue
1.
Stimulates lipolysis
2.
Release of free fatty acids into blood
Pancreas
1.
Inhibits insulin secretion
2.
Stimulates glucagon secretion
Cardiovascular System
64
ANAT 628
Adrenal Medulla
1.
F.
H.
VI.
a)
Increase heart rate
b)
Increase stroke volume
2.
Arterial vasoconstriction, except coronary and skeletal
muscle arteries
3.
Vasodilation of coronary and skeletal muscle arteries
a)
Increase systolic pressure
b)
Minimal effect on diastolic pressure
Lungs
1.
G.
Increase cardiac output
Bronchodilation
CNS
1.
General excitatory effect
2.
High state of arousal/alertness
GI-Tract & Urinary Tract
1.
Inhibit GI activity
2.
Constrict urinary bladder sphincter
3.
Relax muscle in body of the urinary bladder
Metabolism
A.
Deamination
1.
B.
O-Methylation
1.
C.
Monoamine Oxidase (MAO)
Catecholamine O-Methyl Transferase (COMT)
Target tissue uptake
65
ANAT 628
D.
VII.
Adrenal Medulla
Excretion in urine
Pathologies
A.
Pheochromocytoma
66
67
MALE REPRODUCTIVE SYSTEM
I.
Testis
A.
B.
Location
1.
Scrotum
2.
Temperature
Seminiferous Tubules
1.
Sertoli cells
a)
C.
Function
(1)
Nurse cells
(2)
Blood-Testis Barrier
(3)
Androgen Binding Protein
(4)
Inhibin
Interstitial Cells (of Leydig)
1.
Location
2.
Testosterone production and secretion
a)
Sex Hormone Binding Globulin (SHBG)
Copyright 1999, Richard F. Laherty, Ph.D.
ANAT 628
Male Reproductive System
3.
Actions
a)
II.
Reproductive Tract
(1)
Differentiation in utero
(2)
Maturation at puberty
(3)
Maintenance of reproductive tract
b)
Secondary sex characteristics
c)
Libido
d)
Spermatogenesis
e)
Protein anabolic
f)
Pubertal growth spurt
g)
Increased activity of sebaceous glands
Spermatogenesis
A.
Meiosis
68
ANAT 628
B.
C.
Male Reproductive System
1.
Spermatogonia
2.
1 Spermatocytes
3.
2 Spermatocytes
4.
Spermatids
5.
Spermatozoa
Spermiogenesis
1.
Spermatids
2.
Spermatozoa
Hormonal Requirements
1.
Testosterone
a)
Luteinizing Hormone (LH)
(1)
2.
III.
IV.
Side Chain Cleavage Enzyme
Follicle Stimulating Hormone
Sperm Maturation
A.
Epididymis
B.
Capacitation
Endocrine regulation
A.
Hypothalamus
1.
B.
Gonadotropin Releasing Hormone (GnRH)
Anterior Pituitary
1.
Follicle Stimulating Hormone (FSH)
2.
Luteinizing Hormone (LH)
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ANAT 628
C.
Male Reproductive System
Testis
1.
Testosterone
2.
inhibin
V.
Puberty
VI.
Accessory Sex Organs
A.
B.
C.
VII.
Prostate
1.
Location
2.
Product
Seminal Vesicle
1.
Location
2.
Product
Bulbourethral Gland
1.
Location
2.
Product
Male Sexual Response
A.
Penis
1.
Structure
2.
Erection
B.
Emission
C.
Ejaculation
VIII. Pathology
A.
Impotence
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ANAT 628
B.
Male Reproductive System
Primary testicular failure
1.
Leydig cells
2.
Seminiferous tubule dysgenesis
a)
Klinefelter’s syndrome
C.
Cryptorchidism
D.
Turner’s syndrome
E.
Male infertility
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72
FEMALE REPRODUCTIVE SYSTEM
I.
II.
Ovary
A.
Location
B.
Germinal epithelium
C.
Cortex
D.
Medulla
E.
Mesovarium
F.
Follicles
G.
Morphology changes constantly
Ovarian Cycle
A.
Follicular Phase
1.
Primordial Follicles
a)
Primary oocyte
(1)
Arrested first meiotic prophase
b)
Follicle cells
c)
About 1,000,000/ovary at birth
(1)
Approximately 500,000/ovary at puberty
2.
Group of primordial follicles recruited to begin development
each cycle.
3.
Primary Follicles
a)
Oocyte enlarges
b)
Follicle cells enlarge
Copyright  1999, Richard F. Laherty, Ph.D.
PHYS 628
Female Reproductive System
(1)
Now known as granulosa cells
(2)
Divide (mitosis), follicular growth
c)
Development of zona pellucida
d)
Formation of Theca
(1)
(2)
Theca interna
(a)
Androgen producing cells
(b)
Analogous to interstitial cells of the testis
Theca externa
(a)
4.
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Connective tissue capsule
Secondary Follicle
a)
1mm-1cm in diameter
b)
Oocyte continues to enlarge
c)
Granulosa cells continue to divide
d)
Granulosa cells begin secreting fluid within the
follicle
(1)
Follicular Fluid
e)
Fluid-filled spaces coalesce to form a single fluidfilled cavity, the antrum.
f)
Dominant follicle emerges
(1)
g)
Produces estradiol
Estradiol biosynthesis
(1)
Theca interna
(a)
(2)
Produces androstenedione
Granulosa cell
PHYS 628
Female Reproductive System
(a)
5.
B.
C.
Aromatizes androgen to estradiol
h)
Cumulus oophorus
i)
Corona radiata
Mature (Graafian) Follicle
a)
> 1 cm in diameter
b)
Cumulus oophorus and oocyte separate from
follicle wall and float free in the follicular fluid.
c)
Primary oocyte completes first meiotic division
and enters second meiotic division. Second
meiotic division is halted in metaphase. Cell is
now a secondary oocyte.
d)
Follicle continues to produce estradiol
Ovulation
1.
Enzymatic dissolution of follicle wall.
2.
Secondary oocyte and follicular fluid expelled
Luteal Phase
1.
Corpus hemorrhagicum
2.
Corpus luteum
3.
a)
Granulosa and theca interna cells
b)
Invade the remainder of the follicle
c)
Steroid production
(1)
Progesterone
(2)
Estradiol
Luteolysis
a)
Regression of the corpus luteum
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PHYS 628
Female Reproductive System
b)
Preprogrammed
(1)
c)
D.
III.
After 14 days unless “rescued” by chorionic
gonadotropin
Corpus Albicans
Atresia
Hormonal Control of the Ovarian Cycle
A.
Hypothalamus
1.
B.
Anterior Pituitary
1.
2.
C.
GnRH
LH
a)
Theca Interna
b)
Side-Chain Cleavage Enzyme
c)
Androgen production
d)
Ovulation
FSH
a)
Granulosa cell
b)
Follicular development
c)
Aromatase
Ovary
1.
Follicular Phase
a)
Estradiol Production
(1)
Requires 2 cell types
(2)
Theca Interna cell
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PHYS 628
Female Reproductive System
(a)
(3)
3.
Aromatizes androgen to estradiol
b)
Estradiol necessary for follicular development
and growth
c)
Estradiol also necessary for endometrial
proliferation
d)
Estradiol negative feedback on LH & FSH
production
e)
Inhibin
Periovulatory
a)
Estradiol elevated for a period of time
b)
Estradiol becomes a positive feedback effector
c)
Stimulates anterior pituitary to secrete huge surge
of LH
d)
Signal for ovulation
Luteal Phase
a)
Corpus Luteum
(1)
(2)
D.
Androgen
Granulosa cell
(a)
2.
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Inhibin
Progesterone
(a)
Stimulates endometrial function
(b)
Negative feedback effector on hypothalamus and
pituitary
Estradiol
(a)
Aids endometrium
(b)
Returns to being a negative feedback effector
PHYS 628
Female Reproductive System
1.
E.
IV.
Heterodimer,  & 
Activin
1.
F.
77
Homodimer, 2 -Inhibin
Relaxin
Menstrual Cycle
A.
Uterus
1.
B.
D.
E.
F.
a)
Functional layer
b)
Basal layer
Menstrual phase (1-5)
1.
C.
Cyclic changes in the endometrium
Functional layer is sloughed off
Resurfacing (5-6)
1.
Growth of endometrium from basal glands
2.
Estradiol
Proliferative phase (6-14)
1.
Significant growth of endometrium lining and stroma
2.
Estradiol dependent
Secretory phase (14-28)
1.
Uterine glands become functional
2.
Progesterone response
3.
Late secretory phase endometrium shows signs of ischemia
Menstrual phase (1-5)
PHYS 628
V.
Female Reproductive System
1.
Stimulated by withdrawal of progesterone and estrogen
2.
Coiled arterioles spasm, causing ischemia distal to the
arteriole
3.
Endometrial tissue dies from ischemia
4.
Vessel walls rupture, allowing blood to erode the functional
layer of the endometrium
5.
PMS
Puberty
A.
Menarche
B.
Tanner’s stages
VI.
Menopause
VII.
Disorders of the Female Reproductive System
A.
Amenorrhea
1.
Very non-specific symptom
2.
Primary
3.
Secondary
4.
B.
a)
Ovarian cysts
b)
Polycystic ovarian disease
Tertiary
a)
Prolactinoma
b)
Anorexia nervosa
c)
Athlete
Endometriosis
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PHYS 628
Female Reproductive System
C.
Dysmenorrhea
D.
Menorrhagia
E.
Oligomenorrhea
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80
PREGNANCY
I.
Human Chorionic Gonadotropin
A.
Produced by the syncytiotrophoblast
B.
Glycoprotein
1.
Member of the glycoprotein family
2.
2 peptide chains
a)

(1)
b)

(1)
C.
D.
II.
Essentially identical to that of other glycoprotein
hormones
Gives the hormone its specificity
Binds to and activates LH receptors
1.
cAMP is second messenger
2.
Mimics the actions of LH
a)
Stimulates Side-Chain Cleavage enzyme
b)
Rescues the corpus luteum
c)
Stimulates the corpus luteum during first
trimester
Basis of the pregnancy test
Placental Lactogen (Chorionic Somatomammotropin)
A.
Produced by the syncytiotrophoblast
B.
Protein hormone
Copyright  1999, Richard F. Laherty, Ph.D.
PHYS 628
C.
Female Reproductive System
1.
Member of prolactin, growth-hormone family
2.
Common ancestor
Originally named for its lactogenic activity
1.
D.
III.
IV.
V.
Binds to and activates prolactin receptors
Seems to function primarily as a growth hormone for the
developing fetus.
Estrogen
A.
Estriol secreted in the greatest quantity.
B.
Complicated biosynthesis.
1.
Syncytiotrophoblast produces progesterone
2.
Progesterone converted to DHEA-S by fetal adrenal
3.
Syncytiotrophoblast metabolizes DHEA-S to estriol and
estradiol
Progesterone
A.
Produced by the syncytiotrophoblast
B.
Hormone necessary for the maintenance of pregnancy
Other
A.
Relaxin
1.
Produced by the ovary
2.
Similar to insulin in structure
3.
Acts to ripen the cervix and to relax the pubic symphysis
B.
Other pituitary hormones
C.
Releasing factors
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PHYS 628
VI.
1.
Produced by the cytotrophoblast
2.
Essentially all the releasing factors produced by the
hypothalamus
Parturition
A.
Sex steroids
B.
Oxytocin
C.
Prostaglandins
D.
Catecholamines
E.
VII.
Female Reproductive System
1.
-agonists stimulate uterine contraction
2.
-agonists inhibit uterine contractions
Corticosteroids
Lactation
A.
Sex steroids
B.
Prolactin
C.
Oxytocin
VIII. Complications during Pregnancy
A.
Gestational Diabetes
B.
Preeclampsia
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