Endocrinology and Reproduction
Lecture 1 : Chapter 5 – General Principles of Endocrinology
The Endocrine System
-Ductless glands, secrete hormones & travel through blood to all cells
Target cells have receptors, bind specific hormones
Regulate/direct particular functions
o Rates of enzymatic reactions
o Transport ions/molecules across cell membrane
o Gene expression & protein synthesis
Regulate metabolism, H20 & electrolyte balance
Induce adaptive changes help body cope with stressful situations
Promote growth and development
Plasma concentration of hormone depends on:
1) Hormone’s rate of secretion by endocrine gland (major factor for all hormones)
2) Extent of binding to plasma proteins (for lipophilic)
3) Rate of metabolic inactivation & excretion (all hormones)
Solubility Highly water soluble Poorly soluble in water
Low lipid solubility High lipid solubility
Examples Peptide hormones & catecholamines Steroids & thyroid hormone
Release and Stored in granules; released by Released upon synthesis; diffuse
uptake exocytosis across membrane
Circulation Unbound form Bound to carrier protein
Signal Bind to surface membrane receptors, Bind to nuclear receptors:
transduction use second-messenger system. transcription/protein synthesis.
Nervous System vs Endocrine System
Rapid, precise responses Slower response
Brief in duration Longer in duration
Target tissues are muscles and glands Targets many tissues in the body Hydrophilic Hormones
1. Binding of extracellular messenger (first messenger) to surface membrane receptor activates (by G
protein intermediary) adenylyl cyclase (membrane bound enzyme.
2. This converts intracellular ATP cyclic AMP.
3. Acts as intracellular second messenger, triggering cellular response by activation protein kinase A.
4. Protein kinase A phosphorylates an intracellular protein.
5. Phosphorylation induces a change in the shape and function of the protein.
6. Altered protein accomplishes cellular response dictated by the extracellular messenger.
1. A lipophilic hormone diffuses thru plasma & nuclear membranes of target cells, binds with a nuclear
receptors specific for it.
2. Receptor complex binds with the hormone response element, (specific segment of DNA).
3. DNA binding activates specific genes, which produce complementary mRNA.
4. mRNA leaves the nucleus.
5. In the cytoplasm, mRNA directs synthesis of new proteins.
6. These, either enzymatic or structural, accomplish target cell’s ultimate response to the hormone.
-Most commonly due to abnormal plasma concentrations of a hormone (inappropriate secretion).
Hyposecretion: too little secreted.
o Primary – abnormality within gland. Genetic, dietary, chemical, immunologic, cancer, etc.
o Secondary – normal gland but too little hormone secreted; deficiency of tropic hormone.
Hypersecretion: too much secreted
o Causes: tumors; immunologic factors.
o Primary – abnormality within gland.
o Secondary – excessive stimulation from outside the gland.
Lecture 2: Hypothalamus and Pituitary
Hypothalamus and Pituitary
Pituitary: small gland at base of brain, connected to hypothalamus by thin connecting stalk.
Two anatomical and functionally distinct lobes
Release of hormones form both anterior and posterior pituitary is controlled by hypothalamus.
Posterior Pituitary (composed of nervous tissue – the neurohypophysis)
Stores and releases two small peptide hormones
Vasopressin: conserves water.
Oxytocin: stimulates uterine contraction & milk ejection.
Anterior Pituitary (composed of glandular epithelial tissue – the adenohypophysis)
Synthesizes and secretes six different hormones (peptides), mostly tropic – stimulate another gland:
Thyroid-stimulating hormone (TSH): secretion of thyroid hormone.
Adenocorticotropic hormone (ACTH): secretion of cortisol by adrenal cortex.
Follicle-stimulating hormone (FSH): growth and development of ovarian follicles; promotes secretion of
estrogen by ovaries. Required for sperm production.
Leutinizing hormone (LH): stimulates ovulation/luteinization; stimulates ovarian steroid secretion.
Testosterone secretion in males.
Growth hormone (GH): responsible for regulating body growth by stimulating somatomedin (IGF-1).
Not a tropic hormone: Prolactin (PRL). Enhances breast development and milk production in females. Hypothalamic Hypophysiotropic Hormones
1. Hypophysiotropic hormones (releasing & inhibiting hormones) produced by neurosecretory
neurons in the hypothalamus enter hypothalamic capillaries.
2. Capillaries rejoin & form hypothalamic-hypophyseal portal system, link to the anterior pituitary.
3. Portal system branches into the capillaries of the anterior pituitary.
4. The hypophysiotropic hormones leave the blood across the anterior pituitary capillaries & control
the release of anterior pituitary hormones.
5. Stimulated by the appropriate hypothalamic releasing hormone, the anterior pituitary secretes a
given hormone into these capillaries.
6. The anterior pituitary capillaries form a vein, through which the anterior pituitary hormones leave
for ultimate distribution throughout the body by the systemic circulation.
Hypersecretion: excess hormone
o Tumors or cancer, grave’s disease (increased thyroxin or hyperthyroidism)
Hyposecretion: not enough hormone
o Iodine deficiency leading to hypothyroidism, type 1 diabetes (insulin deficiency)
Primary or secondary?
-Primary originates in final endocrine organ within the axis.
Hypercortisolemia due to adrenal tumour, both hypersecretion and negative feedback present!
-Secondary originates in an ‘upstream’ component of the axis.
Hypercortisolemia due to an ACTH secreting tumour of the pituitary.
Accompanied by hypersecretion of the tropic hormone, and hypothalamic-pituitary axis
response to lack of negative feedback is normal?
o Yes; then it is primary.
o Not; then it is secondary.
Lecture 3 – Thyroid Gland
Consists of two lobes of endocrine tissue joined in the middle by a narrow portion of glands
o Arranged into hollow spheres
o Functional unit called a follicle
o Lumen of follicle filled with colloid
Colloid filled follicles surrounded by follicular cells
C cells: come into play with calcium balance. Produce a hormone called calcitonin. Scattered
throughout thyroid gland.
Number refers to the number of iodides attached to the hormone. Synthesis of these hormones
involves tyrosine, the building block of thyroid hormone & involves iodation.
Tetraiodothyronin (T4 or thyroxine) Tri-iodothyronin (T3)
Thyroid Hormone Synthesis
-Synthesized on protein called thyroglobulin, on follicular cells
-Tyrosine-containing thyroglobulin is exported from follicular cells into colloid.
-Thyroid cells captures iodine from blood and transfers it into colloid (active transport) where it
attaches to tyrosine. Moves up conc. gradient because this is energy dependent.
-Iodinated tyrosine molecules are coupled to form thyroid hormones.
Thyroid Hormone Secretion
Thyroid hormones remain in colloid until they split off and are secreted
o Usually enough thyroid hormone stored to supply body’s needs for several months.
o Follicular cells phagocytize thyroglobulin-laden colloid
o Process free T3 and T4 to diffuse across plasma membrain and into blood.
o Most produced is T4 converted to T3.
Effects of Thyroid Hormone
Main determinant of basal metabolic rate
Influences synthesis and degradation of carbohydrate, fat and protein
Increases target-cell responsiveness to catecholamines
Increases heart rate and force of contraction
Essential for normal growth
Plays a crucial role in normal development of nervous system.
o Cretinism: limited intelligence, severely retarded growth and no normal nervous system.
o TRH (secreted from hypothalamus, only 3 amino acids): impossible to measure so we
focus on TSH secretion.
o TSH (pituitary): stimulates thyroid to increase hormone synthesis & secretion Affects
metabolic activity of almost every body cell.
Negative feedback loop
Abnormalities of Thyroid Function
o Primary: e.g. Hashimoto’s – autoimmune. Thyroid gland no longer capable of
synthesizing thyroid hormone. MOST common cause.
o Secondary: deficiency in TRH or TSH secretion (or both). Much less common.
o Another common: inadequate dietary supply of iodine. Not a problem in Western world.
Myxedema: hypothyroidism in adults. B/c people with hyperthyroidism often retain water.
o Undiagnosed hypothyroidism from birth = physical and mental retardation.
o TSH measured to test for low levels. If there’s not enough thyroid hormone to stimulate
metabolism of cells, there isn’t enough to keep TSH in check therefore TSH is elevated. Hypothyroidism Symptoms
-Slow metabolic rate; weight gain -Nervousness or irritability
-Cold intolerant -Fatigue or muscle weakness
-Depression -Trouble sleeping
-Effects on the nervous system (slowed -Heat intolerance
reflexes, slow speech and thought -Hand tremors
processes and feelings of fatigue) -Rapid and irregular heartbeat
-Slow heart rate (bradycardia) -Frequent bowel movements or diarrhea
-Weight loss without loss of appetite
o Autoimmune (Graves disease): antiboides chronically stimulate TSH receptors
o Thyroid nodules: adenomas that produce thyroid hormone
o Thyroiditis: initial phase cause leakage of thyroid hormone. Subsequently hypothyroid
o Latrogenic: overmedication of hypothyroidism
o TSH secreting adenoma (rare)
Treatment of Thyroid Disease
Hypothyroidism: thyroid replacement or iodine (if deficient)
Hyperthyroidism: surgical removal of portion of over-secreting thyroid. Administration of
radioactive iodine. Antithyroid drugs (interfere with synthesis).
Hypothalamic – Pituitary Adrenal Axis
Embedded above each kidney in a capsule of fat
Composed of two endocrine organs
o Adrenal cortex: outer portion, secretes steroid hormones.
o Adrenal medulla: inner portion, secretes catecholamines
Cortex division into 3 structures:
Zona glomerulosa, Zona fasciculate, Zona reticularis
Categories of Adrenal Steroids
o Aldosterone: promotes sodium reabsorption and potassium release.
o Influence mineral balance, Na+ and K+ balance
o Primarily cortisol
o Major role in glucose metabolism as well as in protein and lipid
o Androgens or estrogens
o Identical or similar to those produced by gonads
o Most abundant & important is dehydroepiandrosterone (DHEA, male “sex” hormone) Cortisol
Spares glucose to be used by the brain: inhibits glucose uptake by many tissues but not brain.
Promotes protein breakdown, primarily in muscle
Facilitates lipolysis (both in fat cells and in the liver)
Key role in adaptation to stress
o Regulated by negative-feedback loop involving hypothalamic CRH and pituitary ACTH
o Diurnal rhythm
o Regulated by exteroceptive cues (outside such as light or stress). Has a major impact on
cortisol secretion via hypothalamic pituitary axis.
Integrated Stress Response
Generalized response to any factor that overwhelms the body’s ability to maintain homeostasis.
o Coordinated by the hypothalamus.
Activation of sympathetic nervous system accompanied by epinephrine secretion.
Activation of CRH-ACTH-cortisol system helps body cope by mobilizing metabolic resources.
Adrenal medulla is stimulated to release epinephrine, effects bp & HR.
Hypothalamic pituitary adrenal axis activated
Elevation of blood glucose and fatty acids
Maintenance of blood volume and blood pressure
o Increased activity of renin-angiotensin-aldoesterone system & vasopressin secretion.
Glucocortacoids widely used therapeutically.
o Anti-inflammatory: e.g. arthritis.
o Immunosuppresin: allergic disorders & organ transplant rejection.
Adrenal Sex Hormones
Secretes both male and female sex hormones in both sexes.
Androgen: Dehydroepiandrosterone (DHEA)
o Probably most important sex steroid produced by adrenal gland
Effects masked by testicular testosterone in males.
Physiologically significant in females where it governs:
Puberty: Growth of pubic and axillary hair, growth spurt, libido.
Increase in cortisol = Cushing’s syndrome
Adrenal tumor that autonomously secretes cortisol
Pituitary tumour that autonomously secretes ACTH: majority of Cushing’s syndrom.
Features of Cushing’s
-Obesity. Trunkal adiposity as cortisol stimulates lipolysis = redistribution of fat to abdomen.
-Moon face, buffalo hump: deposition of fat on upper back.
-Stria: pigmented lines due to breakdown of collagen (caused by high cortisol levels).
-Hyperpigmentation makes stria more obvious.
-Increased hair growth. NOTE: resolution of symptoms when high cortisol levels are resolved.
-Treatment w/ glucacorticoid therapy can lead to side effects resembling Cushing’s.
Opposite of Cushing’s
o Autoimmune destruction of adrenal cortex (e.g Tuberculosis)
o Aldosterone deficiency: hyperkalemia and hyponatremi, water loss=hypovolemia.
o In primary ALL adrenal hormones reduced. Sex steroids, cortisol lower, aldosterone.
o Cortisol deficiency: poor response to stress. Hypoglycemia.
o Not enough CRH (corticotropin-releasing hormone) or ACTH
o Only cortisol affected (b/c ACTH has nothing to do with aldosterone or sex hormones).
o ONLY hypocortisolemia
Weight loss, anorexia, increase of ACTH secretion.
Hypotension due to aldosterone deficiency (don’t have this in secondary).
Hyperpigmentation. Increase of ACTH secretion.
Why would you not have these with secondary?
Think about synthesis of ACTH. Does the pituitary respond normally in primary adrenal insufficiency?
Responding normally means is ACTH secretion increased. Always think about negative feedback. With
primary (Addison’s), destruction of adrenal cortex, loss of negative feedback and response is to
increase secretion of ACTH (A LOT). Because it is not able to stimulate adrenal gland which is no longer
there. With secondary problem results in ACTH being very low. Still very low negative feedback but
pituitary doesn’t respond accordingly.
Might be asked: what features are present in primary but not secondary?
Endocrine Control of Fuel Metabolism
Fuel metabolism/intermediary metabolism
o Breakdown, synthesis & transformation of large macromolecules.
Nutrients broken down thru digestions into smaller absorbable molecules
o Proteins amino acids
o Carbohydrates monosaccharides (mainly glucose)
o Fats (triglycerides) monoglycerides and free fatty acids
Synthesis of larger organic macromolecules from small organic subunits, usually require ATP
Reactions result in
o Manufacture of materials needed by the cell
o Storage of excess ingested nutrients
Breakdown/degradation of large, energy rich organic molecules within cells (protein, fat)
o Hydrolysis: large cellular molecules smaller subunits o Oxidation: smaller subunits to yield energy for ATP production
Gylcogenesis – formation of glucose
Glycogenolysis – breakdown of glucose (will increase glucose conc. in blood)
Interconversions Among Organic Molecules
Essential nutrients (amino acids and vitamins)
Excess circulating glucose: stored in liver & muscle as glycogen. Once these stores are “full”,
transformed into fatty acids + glycerol – adipose tissue.
Excess circulating fatty acids become incorporated into triglycerides.
Excess amino acids converted to glucose and fatty acids.
Comparison of Absorptive (FED) and Postabsorptive (FASTED) States
Postabsorptive = 24hr fast or longer
Metabolic Fuel Absorptive State Postabsorptive State
Carbohydrate Glucose & fat providing major Glycogen degradation and depletion. Glucose
energy source. Glycogen synthesis sparing to conserve glucose for the brain.
and storage. Excess converted & Production of new glucose through
stored as triglyceride fat. gluconeogenesis.
Fat Triglyceride synthesis and storage. Triglyceride catabolism. Fatty acids providing
major energy source for non-glucose-
Protein Protein synthesis. Excess converted Protein catabolism. Amino acids used for
and stored as triglyceride fat. gluconeogenesis.
Glycogen depleted fairly quickly.
Ketones can be used by brain as energy source in extreme conditions.
Abosorptive state will result in amino acid conversion and conversion of fat.
In a fast, proteins broken down into amino acids, which can convert into glucose for brain.
Role of Key Tissues in Metabolic States
o Primary role in maintaining normal blood glucose levels, in response to insulin.
o Principal site for metabolic interconversion such as gluconeogensis.
o Primary site where energy is stored in the form of fat
o Important in regulating fatty acid levels in the blood.
o Primary site of amino acid storage
o Major energy user
o Normally can only use glucose as energy source, but also ketones.
o Does not store glycogen
It is mandatory that blood glucose levels be maintained
o Endocrine cells – Islets of Langerhans
B (beta) cells: site of insulin synthesis and secretion
A (alpha) cells: produce glucagon D (delta) cells: pancreatic site of somatostatin synthesis
PP cells: least common cells, secrete pancreatic polypeptide.
Homeostatic Control of Fuel Metabolism
Endocrine pancreas secretes insulin and glucagon. Fuel metabolism is controlled primarily by the ratio
of these hormones.
Pancreatic duct: enzymes enter duodenum through this duct.
We’re going to talk about islet cells, depicted in cartoon form in purple image.
In Islet cells you find 4 cell types (alpha, beta, delta, PP)
Outside Islet of Langerhans you find endocrine cells.
o Remember: endocrine HAVE duct, exocrine lack a duct.
Promotes cellular uptake of glucose, fatty acids, and amino acids and enhances their conversion
into glycogen, triglycerides and proteins.
o Lowers blood conc. of these small organic molecules.
Secretion is increased during absorptive state
o Primary stimulus for secretion is increase in blood glucose concentration. Glucose low in
postabsorptive and high after meal.
Mobilizes energy-rich molecules from storage during post-absorptive state.
Secreted in response to fall in blood glucose on pancreatic alpha cells.
Only increases between meals or 24hrs after a meal
Generally opposes actions of insulin
Stimulus for secretion is decrease in blood glucose levels
o It starts processes to prevent glucose conc. from falling any further, or to raise them.
A lack of insulin (type 1 diabetes) is catastrophic
o You can survive without glucagon, not as important as insulin in terms of metabolic
processes. It’s more for fine-tuning.
Excess of glucagon can aggravate hyperglycemia – diabetes.
Glucagon Is Dominant in the Fasted State
Antagonistic to most actions of insulin, resulting in catabolic state in the body.
Increased glucagon = ketogenesis = gluconeogenesis = glycogenolysis.
Glucose Uptake by Adipose Tissue and Resting Skeletal Muscle is Insulin dependent
In the absence of insulin, glucose cannot enter cell.
Insulin Enables Glucose Uptake by Adipose Tissue and Resting Skeletal Muscle
Exocytosis of GLUT4
Glucose enters cell through facilitated transport by GLUT4
Insulin Indirectly Alters Glucose Transport in Hepatocytes in Fed State
Glut 2 is not insulin dependent
Signal cascade increases hexokinase Phosphorylation of glucose keeps intracellular glucose con low so glucose can move down con
Glucose Transport in Hepatocytes in Fasted State
Insulin conc is low; hexokinase is low