Glen Gross
Intro to Endocrine
3/3/2014
General Properties of hormones:
• Secreted by endocrine glands and tissues
• Three types of hormones:
Protein
Steroid
Amine
• Thyroid
• Catecholamies
• Exert their effects at very small concentrations (nano- to pico-molar levels)
• Bind carrier proteins in serum
• Have endocrine, paracrine and autocrine effects
• Act on receptors on target cells
• Activate secondary messenger systems and/or transcription in target cells
• Critical in many body systems and functions:
Growth and development
Respiration, excretion, metabolism
Reproduction
Hierarchy of the Endocrine System
1. Involves:
a. hypothalamus
b. pituitary gland
c. a third endocrine gland and other hormones
2. classes:
a. releasing or inhibiting hormones
b. trophic hormones
c. final hormones
d. target cells
The hypothalamus:
1. function:
a. is the integrator of many homeostatic and reproductive signals
2.. secretion of its hormones:
a. regulates anterior pituitary hormone production and secretion
3. hypothalamic neurons:
a. extend into posterior pituitary
b. hormones are released from the neurons
4. infundibulum:
a. is the stalk that connects the pituitary to the brain
5. posterior pituitary:
a. is an extension of nueral tissue
6. anterior pituitary:
a. is the true endocrine gland
b. derived from epithelium
How the hypothalamus interacts with the posterior pituitary:
1. hypothalamic neurons produce the following hormones:
a. oxytocin
b. vasopressin
i. these project into the posterior pituitary
2. appropriate signals  hormone release from the hypothalamic neurons:
a. from the posterior pituitary into the general circulation
3. target cells see the hormone rapidly after their release
Hypothalamic interaction with the posterior pituitary:
1. hormone is made and packaged in the cell body of the neuron
2. vesicles are transported down the cell
3. vesicles containing hormones are stored in the posterior pituitary
4. hormones are released into the blood of the general circulation
a. hormones bind specific target cells
Hypothalamic interaction with the anterior pituitary:
1. hypothalamic neurons secrete releasing or inhibitory hormones into the
hypothalamo-hypophyseal portal system
2. portal system bathes the anterior pituitary cells
3. hypothalamic hormones bind to receptors on the anterior pituitary cells
4. anterior pituitary cells  release their hormones into the general circulation
and produce more hormones
5. target cells:
a. are within 1/3 of the endocrine gland
b. are exposed to the anterior pituitary hormones
6. the process is slow compared to posterior pituitary response times
7. the heirarchy is important:
a. of the hypothalamic-pituitary endocrine axis
=pituitary
Regulation of hormone secretion:
1. negative feedback:
a. most common mechanism
b. limits the amount of hormone release
i. the thyroid hormone curtails release of thyroid-releasing hormone and thyroid
stimulating hormone
2. positive feedback:
a. rare
b. reinforces a snowball effect  resulting in more hormone secretion
i. ovarian estrogen increases the effects of ovulation
Regulation of hormone secretion with a Hypothalamo-Pituitary-Endocrine Axis:
1. negative feedback is involved
2. short loop feedback:
a. excess of hormone produced in the pituitary (trophic hormone) runs from the
pituitary back to inhibit the hypothalamus
3. long loop feedback:
a. excess hormone produced by the peripheral endocrine glands will inhibit further
production in both the pituitary and hypothalamus
Protein/Peptide Hormone Synthesis and Secretion:
1. preprohormone:
a. synthesized and cleaved into  prohormone
i. takes place in the rough endoplasmic reticulum (RER)
2. prohormone:
a. moves into the golgi apparatus
b. enzymatic cleavage takes palce to produce  mature hormone
3. mature hormone:
a. packaged into secretory granules
4. with appropriate signal release:
a. the secretory granules fuse with the plasma membrane  released by exocytosis
5. protein hormones:
a. are soluble in water
b. may be transported by carrier proteins
i. protect them from metabolic breakdown
Peptide hormones are made as inactive preprohormones:
1. preprohormones:
a. a large, inactive peptides
b. have a signal sequence
i. directs movement into the rough endoplasmic reticulum
c. may have additional peptide fragments
Steroid hormone synthesis and secretion:
1. derived from cholesterol either from:
a. plasma membrane
b. synthesized from acetate
2. converted to final product by enzymatic action
3. enzyme location:
a. mitochondria
b. smooth ER
4. steroid hormones are produced and secreted without storage
5. steroid hormones pass across cell membranes by diffusing down their
concentration gradients
6. steroid hormone additional features:
a. are NOT water soluble
b. are bound to carriers and transport proteins
7. the free steroid hormone:
a. enters the target cells
Synthesis of steroid hormones:
1. steroid hormones are synthesized by:
a. gonads
b. adrenal cortex
c. placenta
Amine Hormone Synthesis and Secretion:
1. catecholamines:
a. have properties similar to protein hormones
2. examples:
a. dopamine
b. norepinephrine
c. epinephrine
i.. are produced in neurones:
ii. packaged into vesicles
iii. released intermittently upon demand
4. thyroid hormones
a. acts like steroid hormones:
i. BUT its precursors are stored in vesicles
b. they bind to receptors that belong to the nuclear receptor superfamliy
5. examples:
a. T4 (tetroiodothryonine)
b. T3 (triiodothyronine)
i. synthesized on a protein backbone which is processed in the lysosomes
ii. control of production is based on enzymatic activity and iodine availability
iii. secretion involves diffusion down their concentration gradients
Amine Tyrosine based hormones:
1. tyrosine:
a. catecholamines
i. dopamine, norepinephrine, and epinephrine
b. thyroid hormones
i. T4 and T3
How hormones regulate receptors on target cells:
1. hormones can down-regulate receptor signalling by:
a. decreasing the receptor number
b. decreasing the affinity of receptors for the hormone
c. example:
i. in the breast, elevated estrogen levels reduces the number of estrogen
receptors
2. hormones can up-regulate receptor signalling by:
a. increasing the receptor number
b. increasing the affinity of receptors for the hormone
c. example:
i. in the breast, elevated estrogen leves increases the number of progesterone
receptors
How protein/peptide hormones act on target cells:
1. peptide hormones bind to receptors located in target cell membranes
2. receptor types:
a. tyrosine kinase bind to:
i. insulin
ii. insulin-like growth factors
3. peptide hormone bound receptors:
a. activate secondary messengers
i. guanosine triphosphate binding-proteins (G-proteins)
ii. adenylate cyclase (AC)
iii. inositiol triphosphate (IP3)
iv. calcium-calmodulin (Ca2+)
What do G-proteins do?
1. stimulate adenylate cyclase:
a. produces cAMP
i. provides phosphorylation for use in phosphorylation cascades
2. increase cytoplasmic calcium:
a. releasing calcium from intracellular stores
b. opening calcium channels in cell membranes
i. calcium binds to calcium binding proteins
ii. Ca2+-calmodulin activates kinases and phosphatases
3. activates phospholipase C:
a. produces DAG and IP3
b. IP3 induces calcium release from endoplasmic reticulum
c. DAG induces protein kinase C activity (PKC)  causes phosphorylation cascades
Nuclear Receptor Superfamily:
1. the place where steroid hormones bind:
a. estrogen:
i. receptor ER
b. progesterone
i. receptor PGR
c. androgens
i. receptor AR
d. glucocorticoids
i. receptor GR
e. mineralcorticoids
i. receptor MR
2. transcriptional response:
a. involves formation of hormone-receptor homodimers
Nuclear receptor superfamily:
1. RXR hormone receptor ligands include:
a. thyroid hormones
i. receptor T3R
b. vitamin D
i. receptor VDR
c. fatty acids, eicosanoids (including prostaglandins)
i. receptor PPAR
2. transcriptional response:
a. requires ligand-receptor heterodimer with the retinoid X receptor (RXR)
Why do you need to know about the nuclear receptor superfamily?
1. these receptors are very important drug targets:
a. thyroid supplementation targets T3R
b. glucocorticoid therapies target GR
c. type II diabetes treatments target PPAR
d. vitamin D responses due to VDR
e. progesterone therapy during pregnancy targets PGR
Steroid and Thyroid Hormones:
1. both have receptors which belong to:
a. the nuclear receptor superfamily
2. the receptor-ligand complexes function as transcription factors:
a. binding of the ligand to the receptor  causes dimerization
b. translocation to the nucleas  binding to DNA binding domains
c. regulates promotion and inhibition of transcription and translation of genes
How Steroids and Thyroid Hormones Act on Target Cells:
1. hormones diffuse across the cell membranes:
a. bind to cytoplasmic receptors (steroids and thyroid hormones)
2. hormone-bound receptors  enter the nucleus:
a. form hormone-receptor dimers
3. these dimers are transcription factors:
a. bind to specific DNA sequences and DNA
i. steroid response elements
b. initiates transcription
4. result:
a. production of proteins that have physiologic properties
5. example:
a. in the breast, the estrogen-estrogen receptor dimers stimulate transcription of
progesterone receptors
Nuclear receptor signalling:
1. free hormone dissociates from carrier proteins and enters the cell
2. hormone binds to the cytoplasmic receptor:
a. translocates to the nucleus
3. dimers form:
a. sit down on specific steroid hormone response elements contained in genes
4. transciption of mRNA
5. translation of protiens
6. hormone cellular response
Hormone fates:
1. liver and kidneys role in degradation of circulating hormones:
a. steroid hormones
i. undergo oxidation by liver p450 enzymes in Phase I metabolism
b. carrier proteins
i. protect and extend the life of hormones by protecting them from liver and
kidney metabolism
2. urinary and biliary excretion
3. cellular uptake and degradation:
a. which occurs after the receptor signalling
Hypothalamic hormones are secreted in pulses:
1. pulsatile secretion of the hypothalamic and pituitary hormones:
a. required to prevent desensitization of downstream receptors
2. continuous administration of hormones results in:
a. down-regulation of receptors
b. after a few days, a general reduction in hormone signalling occurs
3. hypothalamic hormone secretion has a circadian rhythm:
a. associated with the sleep cycle
Responses to multiple hormones:
1. response can be:
a. additive
b. synergistic
c. permissive
d. antagonistic
2. cells and tissues are often affected by multiple hormones
3. the effect of multiple hormones can be:
a. additive
b. synergsitc
4. some hormones are permissive:
a. allows for another hormone to exert its full effect
5. some hormones are antagonistic:
a. prevents the action of another hormone
Summary:
1. Hormones biochemistry dictates how they are produced, stored and released
2. Hormone receptor complexes mediate the physiological responses via secondary
messenger systems (peptide hormones) or via transcription (steroids)
3. The endocrine system is organized in a hierarchy.
When the Anterior pituitary is involved, the hierarchy involves the hypothalamus
and usually a tertiary endocrine gland in the periphery that produces a final hormone.
This is called an hypothalamic-pituitary endocrine axis.
Hypothalamic neuron projections into the Posterior pituitary release hormones
directly into circulation and this is the FINAL hormone of action
4. Hypothalamic and pituitary hormones are proteins. Tertiary endocrine
hormones can be either proteins (e.g., insulin) , steroids (e.g., glucocorticoids) or
amino acid (e.g., thyroid hormones) based.
5. Specific and nonspecific carrier proteins bind most hormones.
This increases total serum concentrations (free hormone + carrier bound hormone)
of insoluble hormones (e.g., steroid & thyroid hormones) and
protects hormones from metabolism and excretion.
6. Response rates to protein hormone binding to receptor are generally rapid
(minutes) and to steroid hormones is slow (hours).
7. Hormone removal from circulation involves liver and/or kidney metabolism and
bile or urinary excretion.
8. Hypothalamic hormone secretion is pulsatile and is influenced by circadian
rhythm.
9. One hormone may influence the response of another hormone. Hormones may
be permissive, additive, synergistic or antagonistic.