• Subdiscipline of physiology
• Study of Hormones:
• `````Physiological roles
• `````Cellular sources
• `````Biosynthesis
• `````Chemistry and storage
• `````Factors and mechanisms controlling secretion
• `````Cellular Mechanisms of hormone action
• `````Pathophysiology of endocrine sys. disfunction

One's physical and mental health depended on the balance of the four humors.

This theory lasted until at least the 18th century.

1. Blood
2. Phlegm
3. Black Bile
4. Yellow Bile

• External structure
• Easy accessability
• Interest in human sexuality

• Eunuchs as guards for harems or brothels
• Castrados in church choirs
• Form of punishment and humiliation (Still even today, in some societies)
• Animal castration to improve the palatability of meat

He first wrote "On the Motion of the Heart and Blood in Animals"

 a.k.a. De Motu Cordis

It named the blood as the circulation medium throughout the body, pumped by the heart, in a circuit.

• Successfully transplanted gonads among birds:
• Demonstrating the testes droves maleness and the ovaries drove femaleness.
• Still no awareness of mechanism of secretion into blood at the time.

• The first to report and describe what is now called "internal secretion and humoral integration"
• His Hypothesis: Each gland and organ of the body is a workshop producing secrections, which pass into the blood and influence total body functions

• Conducted the first formal study in endocrinology
• Roosters - Capons : First recorded ablation / replacement experiment on testes.

• Left usually bigger than right
• Age-related, larger left testicle found in younger birds
• More primordial germ cells in left, aquired from right
• Age-related, larger right found in older roosters
• (Similar asymmetry found in ovaries in females)

• Developmental cost of having two large testicles
• `````Metabolic cost of two equally large testicles is too great because of the potent immunosuppressive effect of testosterone.
• `````Greater mass could affect flight
• Right Testis may be primarily compensatory (back-up)
• `````Low degrees of asymmetry suggests right testis has become fully developed to compensate for inadequate left testis
• `````Males in poor health might have larger right testis than left

• Firmly established, through chemical analysis, the idea that blood is altered when it passes through an organ.
• In his research, the liver was the primary organ studied.
• FIRST TO USE THE TERM "INTERNAL SECRETION"!!!!

• first use of tissue extracts in a clinical setting
• injected dog-testes-extracts into himself, claimed rejuvenation
• public interest drove further research

• 1891 - treated hypothyroidism with thyroid extract
• FIRST CLINICAL TREATMENT FOR AN ENDOCRINE DISORDER, EVEN THOUGH THYROID HORMONES HADN'T YET BEEN ELUCIDATED

• 1889 - DIABETES MELLITUS term coined.
• Ablation replacement experiments on dogs/pancreas
• Did not know about insulin yet

• 1902-1905
• Conducted experiments leading to discovery of SECRETIN - THE FIRST DISCOVERED HORMONE!!
• It's considered the "Start of endocrinology"
• S- Coined the term "HORMONE" !!

• Electron Microscopy
• Radioactive Isotopes
• Tissue Culture
• Analytical Methods

• Separation techniques
• Purification techniques
• Synthesis of protein hormones
• Studies on mechanism of hormone actions - PATHWAYS!!

• 1953 
• Determined structure of, and synthesized the first peptide hormones oxytocin and vasopressin/ADH/AVP
• (which are found in the posterior pituitary)

• 1954
• Determined the chemical structure of insulin
• First to determine the structure/sequence of any protein hormone

• 51 Amino Acid residues per molecule
• 2 chains (A&B)
• 1 intrachain disulfide bridge
• 2 interchain disulfide bridges

• 1960
• Discovered ecdysone, insect molting hormone that induces cell nucleus RNA increase (chromosome puffing)
• Showed that hormones could affect DNA / RNA

• 1963
• Synthesized insulin 
• The first protein hormone to be synthesized

• 1957-1960
• Discovered cAMP as a hormone mediator
• Elucidated the mechanism of action of some hormones
• Discovered epinephrine affects liver to induce increase in blood glucose
• 1971 - NOBEL PRIZE!
• "Showed that hormones do not have a direct, but rather an indirect action via intermediates, which regulate, but do not mediate reactions"

• 1950s-1960s
• Elucidated hypothalmic control of the pituitary endocrines
• Discovered releasing factors
• 1st of all was Corticotropin Releasing Factor (CRF)
• Considered the "Fathers of neuroendocrinology"

1977 - Shared NOBEL PRIZE with Berson and Yalow

• 1960
• Developed radioimmunoassay (RIA) techniques
• Allowed for accurate measurements of hormone concentration (picogram/mL);
• Again, insulin was the first measured

1977 - Shared NOBEL PRIZE with Guilleman and Schally

• 1849
• Originated the concept of internal vs external environment
• "milieu interior which is the condition of free and independent life"

• 1932
• Built upon Claude Bernard's concept of milieu interior
• coined the term homeostasis and expanded idea
• steady state condition
• homeostasis is the result of a organized self-regulation
• early idea of fight or flight response

• Process by which organisms maintain the "constancy" of their internal environment in response to changes in their external environment
• Self adjusting mechanism involving feedback regulation (negative more commonly, and positive)
• Works to maintain the internal environment within a narrow range of conditions conducive to life

• Glucose (30-300mg/dL)
• Calcium
• Sodium
• Body Temp
• Blood Volume/Body Fluid levels

• The "Hypothalamus-pituitary-endocrine organ axis"

• The Hypothalamus -> Pituitary -> Endocrine Gland     -> Target Organ -> DESIRED EFFECT

1. The response of the target organs/glands diminishes the original stimulus
2. Output of a pathway inhibits inputs to the pathway
3. Can continue forever
4. Maintains homeostasis

1. Destabilizing stimulus is sensed
2. Hormone secretion is triggered
3. Hormone activity lowers a parameter to bring process back to pre-stimulus state

• Secretion
• Blood clotting
• Muscle contraction
• Thermoregulation
• Nerve signal conduction

Its concentration is maintained within very narrow limits both inside and outside the cell

Its level in the blood is what is regulated by the body

1. Elevation of blood glucose concentration
2. Beta cells in pancreas release insulin
3. Insulin facilitates entry of glucose into cells
4. Blood glucose level falls sufficiently
5. The stimulation for insulin release falls
6. Insulin secretion stops

1. Unstable system
2. It is used to trigger a sudden even / phenomenon
3. Cannot continue forever / always has a limit
4. Does not result in homeostasis
5. Beneficial in only special circumstances
6. Usually terminated by a dramatic event (i.e. Childbirth, Death)

Neuroendocrine Integration

definition and examples

Def: an intertwining of the nervous system and the endocrine system

Ex: Adrenal medulla - releases epinephrine, norepinephrine, and dopamine into the blood.

(It's innervated by the sympathetic autonomic nervous system)

The hypothalamic median eminence,

and the bloodstream. 

1. Endocrine/Neuroendocrine
2. Paracrine 
3. Autocrine
4. Neurocrine
5. Intracrine

Delivery via hormone feedback on the cell of origin in a form of self regulation

(e.g. the ultrashort loop)

Delivery via hormones released into the synaptic cleft by neurons that are in contact with the target cells

(e.g. peptide hormones)

Delivery via hormonal action within a cell

(e.g. steroid hormones acting through intracellular (mostly nuclear) receptors).

1. They must be metabolized rapidly and removed, so FEEDBACK MECHANISMS can operate and cellular functions can be regulated
2. Removal/inactivation of these follows a pattern of exponential decay (kinetics).
3. Its "half-life" is how its longevity is measured
4. Synthetic versions/analogues are designed to have a longer half-life in order to be more effective for longer periods of time than those naturally occuring

1. Peptidases - e.g. cathepsins (proteases): in lysosomes split all the peptide bonds in the molecules
2. Exopeptidases - degrade peptides from the carboxy-terminal OR the amino terminal end.
3. Endopeptidases - e.g. trypsin and chymotrypsin: degrade proteins at specific sites like lysine or arginine, and phenylalanine or tryptophan or tyrosine
4. Deamination or reduction of disulfide bonds (like the ones in insulin) - This occurs in the kidney, liver, and in target cell lysosomes

How can a hormone increase its half-life?

1. Be a steroid hormone (which can hang out in adipose tissue due to the steroids' lipophilicity)

2. Bind to a protein carrier

3. Stay away from the liver and kidney to avoid the 2-phase degradation process

1. Concerted/Additive - Thyroid,  T_3, Growth Hormone works on RNA expression and thus, growth
2. Non-Additive - Epinephrine works on insulin and glucagon, so does cortisol to release more glucose into the bloodstream
3. Synergistic - T₃ and Cortisol, genes affected, somatotropin
4. Permissive - estradiol permits expression of progesterone receptors in oviduct

1. Concentration of hormone in blood and exracellular fluid
    
2. Hormone-receptor interaction (Binding)
    
3. Intracellular signaling mechanisms (Phosphorylation, signal transduction pathway, etc.)
    

• Melatonin
• Cortisol
• Thyrotropin
• Growth hormone

• Core Body Temperature
• Urine Volume
• Cerebral Blood Flow
• Systolic Blood Pressure

It's a consequence of 

1. Feeback Controls

2. Regulated Secretion

3. Limited lifespan of a hormone

1. Circhoral - an hour (testosterone)
2. Ultradian - recurrent periods/cycles repeated during a 24-hour circadian day (sleep, feeding)
3. Circadian - endogenously driven cycle of roughtly 24-hours (Melatonin, corticosteroids)
4. Quotidian (diurnal) - occurs every day (body temperature)
5. Infradian - periods longer than a day (human menstrual cycle)
6. Circatrigintan - a month, approximately (ovulation)
7. Circannual (seasonal) - a year (thyroxine, dog reproduction)