Sarah Margareta Ibrahim Wednesday, January 9th 2013▯
PHGY 210 - Mammalian Physiology II
Lecture 2 - Endocrinology (Part 2 of 6)
Feedback control of Hormone Secretion (Example of Calcium Regulation)
• Hormone secretion is precisely regulated by feedback mechanisms.
• An excess of hormone, or excess hormonal activity, leads to a diminution of hormone
• Conversely, a deﬁciency of hormone leads to an increase in hormone secretion
The example below is negative feedback of regulation of calcium in the circulation - weʼll see
this again this image is just to go over the
concept rather than the details.
• Calcium in the circulation has to be tightly
controlled. We know from physiology that the
bodyʼs use of calcium in all of itʼs cells is more
important than keeping the calcium in the bones.
So maintaining calcium in circulation and its
accessibility to the cells in the body is extremely
physiologically important - itʼs maintained at a
very narrow range under normal physiological
conditions. When itʼs low, parathyroid release
from the parathyroid goes up and then
parathyroid hormone does itʼs thing in bone,
kidney and gut.
• Bone is your calcium repository, your kidneyʼs are your ﬁlters so a physiological decision is
made - how much do we let go in the urine? How much are we going to keep in the
circulation? And of course, the gut is where dietary calcium (cheese, eggs, milk etc.) is
• Under the inﬂuence of parathyroid hormone and downstream events circulating levels of
calcium rise. At that point they start to impinge increasingly on the calcium receptors in the
parathyroid and that shuts down parathyroid production.
Thereʼs this constant sort of argument back and forth - goes down a bit, PTH goes up and
then it goes up, shuts it down and the result is itʼs
homeostatic. Most endocrine systems function this way.
Hormonal Feedback Mechanisms (Example of Control of
• Showing this example because itʼs the HP-end organ axis.
Will see this several times.
• So you have corticotropin releasing hormone (CRH)
(*Note: “trope” is an attraction for something) released by
the hypothalamus impinges upon the pituitary - you get
adrenocorticotropic hormone (ACTH) released and that
goes to interact with itʼs receptors on the surface of the
adrenal glands and that leads to the production of
• Glucocorticoid levels rise and you get a double negative
feedback where you get inhibition of release of CRH and
ACTH at the level of the hypothalamus and the pituitary.
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Endocrine Glands and their Secretions
The following sections (on the different endocrine glands - today weʼll look at the pituitary gland
and the thyroid gland) will be structured like this:
1. Anatomic Location
2. Hormones Secreted
3. Chemical Nature of Hormones
5. Mechanism of Action
6. Control of Release▯
7. Problems ▯
A. The Pituitary Gland
1. Anatomic Location
• Looks like a tiny little punching bag hanging off
of the bottom of your brain
• Two distinctly different tissues (or cell types):
(1) adenohypophysis (a.k.a. anterior
pituitary, or pars distalis) and
(2) neurohypophysis (a.k.a. posterior
pituitary, or pars nervosa).
• Histologically (aka under the microscope), the
anterior pituitary is endocrine tissue.
• The posterior pituitary is neural tissue.
*Aside: Summary of what we will go through in the
next few lectures. Know this for the exam:
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2. and 3. Hormones secreted/Chemical Nature of Hormones
• The posterior pituitary is in this list because the posterior pituitary is effectively an
extension of the hypothalamus (it looks like itʼs separate but itʼs continuous with the
hypothalamus). As far as this course is concerned, the posterior pituitary produces
1. Arginine vasopressin (antidiuretic hormone)
These two are short peptides and somewhere back in evolution there was a gene
duplication event where the primordial oxytocin vasopressin gene somehow was
duplicated and then there was some form of evolution and now we have two
hormones in a large number of organisms that have related structures but largely
distinct physiologies. These are short peptide sequences so you have an oxytocin
gene and arginine vasopressin gene.
• Then there are the other hormones that are produced by the hypothalamus that
impinge upon the anterior pituitary. All of them except for one is different. Prolactin-
inhibiting hormone = dopamine. Most people know dopamine as a neurotransmitter
but it has a double life - it can act as a hormone as well. Dopamine is derived from a
free amino acid called tyrosine. There is no dopamine gene! There are enzymes that
produce dopamine from tyrosine but there is no dopamine gene. All of the other guys
are peptidic - theyʼre peptides (even TRH) meaning theyʼre all coded by genes.
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*Aside: Posterior Pituitary Gland
• Outgrowth of hypothalamus connected by
the pituitary stalk.
• Secretes oxytocin and vasopressin (a.k.a.
antidiuretic hormone ‐ ADH).
• Oxytocin and vasopressin synthesized in
two hypothalamic nuclei (supraoptic
nucleus and paraventricular nucleus ***
Nucleus in this case refers to a set of
neurons (cells) not an actual cell nucleus),
whose axons run down the pituitary stalk
and terminate in the posterior pituitary
close to capillary blood vessels. Posterior
pituitary is a cellular extension of the
• Because they are both peptidic hormones,
they are produced as larger pre- pro-
hormones (these sort of signaling
barcodes that direct them towards the
secretory apparatus). This processing
takes place during a transportation
process down the pituitary stalk such that
by the time they get to the blood system -
the capillary network at the base of the
pituitary, theyʼre in their mature form. At
some point, to get the thing secreted you have to have close apposition of the
neuronal cells with the circulation and this is where this takes place.
• Prohormones processed in secretory granules during axonal transport.
• Mature hormones liberated from the carrier molecules, neurophysins.
• Circulating half lives: 1‐3 minutes (not uncommon because if itʼs turned over rapidly its
easier to control its levels - you want the signal when you need the signal and not
when youʼre done with it)
• Males: no known function, although secreted by posterior pituitary??? Probably
affecting behavior. Love?
• Females: two main functions, both motor.
(i) Parturition (child birth); uterus extremely sensitive to oxytocin at end of pregnancy
(aka, the uterus is producing high concentrations of oxytocin receptors at the end
▯ ‐dilation of the uterine cervix by fetal head causes reﬂex release of
▯ ‐oxytocin then causes uterus to contract, which assists the expulsion of
▯ fetus and later of placenta.
(ii) Milk ejection. In lactating mother: response to the stimulus of suckling.
▯ ‐Oxytocin causes milk ﬁlled ducts to contract and squeeze milk out.
Why would we want to have oxytocin to have a short half life? You donʼt want uterine
contractions after youʼve given birth. Ouch.
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B. Thyroid Gland
1. Anatomic Location
• Located at the back of the trachea (sort of wraps
around the trachea)
• It has this these follicle structures that are ﬁlled with
whatʼs called “colloid”
• 15 to 20g
• Varies size with sex, age, diet, reproductive state,
• Larger in females than males.
• Only 3g of healthy thyroid needed to maintain
euthyroid state (normal thyroid physiology)
• Colloid: major component is thyroglobulin, a large
protein of 700,000 Dalton (so it has 6500 amino
acids so the coding region of the mRna is almost
20,000 bp long - itʼs huge!)
• Only produces a few tyrosine residues
• All of this that takes place is under the control of TSH (thyroid stimulating hormone)
• It is a source of thyroid hormones thyroxine (T4) and triiodothyronine (T3).
• T4 and T3 are split off the thyroglobulin, and enter blood where they bind to special
• Synthesis of thyroglobulin under control of TSH of pituitary gland.
Thyroglobulin provides a type of storage for T4 and T3 prior to release.
2. and 3. Hormones secreted/ Chemical Nature of Hormones
• Thyroid hormones contain iodine
• This introduces a problem because it means that
iodine now becomes an essential part of the diet
(thatʼs why you have sodium iodide in salt)
• Availability of iodine to terrestrial vertebrates
• Cellular mechanisms developed for concentration,
utilization and conservation of iodine in thyroid
Iodide is I itʼs ionic so itʼs not going to get through
the cell membrane so itʼs not going to be absorbed
non-speciﬁcally by every other cell type in the body
it has to be speciﬁcally transported across a
membrane - for that you need a transporter.
• Thyroid follicular cells are able to trap iodide and
transport it across the cell against a chemical
gradient (active transport).
• Youʼve got T4 and T3. The T4 is produced if youʼve got a diiodonated tyrosine ring
which is transferred on to another diiodonated tyrosine ring (see image). The T3 is
produced if a monoiodonated tyrosine ring is transferred onto to a diiodonated
tyrosine ring. You can also get, under conditions of hyperthyroidism, a certain amount
of reverse T3 (which is a marker of hyperthyroidism but is not a biologically active
molecule because it doesnʼt bind to the thyroid hormone receptor at any physiological
• Synthesis of Thyroid Hormones
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Iodide as it crosses the membrane is converted
to iodine (I2). That is the substrate that is used
• Iodine (I2) used for iodination of tyrosine
residues of thyroglobulin (TGB) to form
monoiodotyrosine (MIT) and diiodotyrosine
• Oxidative coupling of two DIT forms thyroxine
(T4), while oxidative coupling of one MIT with
one DIT forms triiodothyronine (T3).
• These hormones are stored linked to
• Tate of all steps of T4 and T3 formation is
increased (and controlled) by TSH levels.
• Control of thyroid activity
• Another negative feedback loop
• Without TSH (or when TSH is low), thyroid has very
low turnover of thyroid hormones. So not much is
• Synthesis and release of TSH controlled upstream by
hypothalamic thyrotropin releasing hormone (TRH) -
obviously produced by the hypothalamus.
So TRH turns on TSH production goes to the thyroid,
interacts with the TSH receptors on the thyroid.
Stimulates all aspects of the thyroid hormone
production. Thyroid levels in the circulation go up and
thereʼs a negative feedback loop that is set up
whereby production of TSH in the pituitary and TRH
by the hypothalamus are attenuated by rising levels
of thyroid hormone.
• When T4 and T3 in blood increase they exert a negative feedback at both
hypothalamic and pituitary levels to decrease release of TRH and TSH.
• TSH interacts with speciﬁc receptors located on follicular cells, leading to
increased production of T4 and T3.
• Example. The TSH receptor is one of those so called G-protein coupled receptor
and TSH binding to cells in the thyroid leads to cyclic AMP (cAMP) and a series of
intercellular second messenger events downstream of it.
• Iodine Deﬁciency (nutritional)
• What happens when this goes wrong? If the tryosineʼs canʼt be iodonated, youʼre
not going to produce thyroid hormone. If youʼre not producing thyroid hormone,
thereʼs no negative feedback loop. If thereʼs no negative feedback loop, TRH goes
up and TSH goes up. So TSH starts pounding on the thyroid - “wake up!” but no
oneʼs home. So the way that they thyroid responds is by becoming hyperplastic (it
gets bigger) as a way to try and make more of this stuff that it canʼt make.
When the supply of iodide is deﬁcient, synthesis of thyroid hormones decreases
and T4 and T3 in circulation decrease.
• Release of TSH increases and the thyroid follicular cells are constantly stimulated.