Transcript Regulating Plasma Hormone Levels

Regulating Plasma Hormone Levels
Factors Involved: Secretion versus Removal
Regulation of Secretion
Metabolic Clearance Rate & Half-life
Role of Carrier Proteins
Role of Glycosylation
Notes on the First Midterm
Gland
Regulatory Hormone
Gland
Blood Hormone
Binding
Transportation
Active Metabolite
Target Cell
Receptor Binding
Signal Transduction
Activation
Response
OR
(-)
A linear control sequence with each
collection of cells secreting a hormone to
control subsequent cells.
Regulation of Hormone Secretion
Sensing and signaling: a biological need is sensed, the
endocrine system sends out a signal to a target cell
whose action addresses the biological need. Key features
of this stimulus response system are:

receipt of stimulus

synthesis and secretion of hormone

delivery of hormone to target cell

evoking target cell response

degradation of hormone
This is relevant to the status of the hormone itself, rather than to
the type of system that regulates it (neural, endocrine,
humoral), as we will see later in the hour.
Control of Endocrine Activity
•The physiologic effects of hormones depend
largely on their concentration in blood and
extracellular fluid.
•Almost inevitably, disease results when hormone
concentrations are either too high or too low, and
precise control over circulating concentrations of
hormones is therefore crucial.
Control of Endocrine Activity
The concentration of hormone as seen by target
cells is determined by three factors:
•Rate of production
•Rate of delivery
•Rate of degradation and elimination
Control of Endocrine Activity
Rate of production: Synthesis and secretion of
hormones are the most highly regulated aspect of
endocrine control. Such control is mediated by
positive and negative feedback circuits, as described
below in more detail.
Control of Endocrine Activity
Rate of delivery: An example of this effect is
blood flow to a target organ or group of target
cells - high blood flow delivers more hormone
than low blood flow.
Control of Endocrine Activity
Rate of degradation and elimination: Hormones,
like all biomolecules, have characteristic rates of
decay, and are metabolized and excreted from the
body through several routes.
Shutting off secretion of a hormone that has a very
short half-life causes circulating hormone
concentration to plummet, but if a hormone's
biological half-life is long, effective concentrations
persist for some time after secretion ceases.
Feedback Control of Hormone
Production
Feedback loops are used
extensively to regulate
secretion of hormones in the
hypothalamic-pituitary axis.
An important example of a
negative feedback loop is seen
in control of thyroid hormone
secretion
Inputs to endocrine cells
Neural control
• Neural input to hypothalamus stimulates
synthesis and secretion of releasing factors
which stimulate pituitary hormone production
and release
Chronotropic control
• Endogenous neuronal rhythmicity
• Diurnal rhythms, circadian rhythms (growth
hormone and cortisol), Sleep-wake cycle;
seasonal rhythm
Episodic secretion of hormones
• Response-stimulus coupling enables the
endocrine system to remain responsive to
physiological demands
• Secretory episodes occur with different
periodicity
• Pulses can be as frequent as every 5-10
minutes
Episodic secretion of hormones
• The most prominent episodes of release occur with a
frequency of about one hour—referred to as
circhoral
• An episode of release longer than an hour, but less
than 24 hours, the rhythm is referred to as ultradian
• If the periodicity is approximately 24 hours, the
rhythm is referred to as circadian
– usually referred to as diurnal because the increase in
secretory activity happens at a defined period of the day.
Circadian (chronotropic) control
Circadian Clock
Physiological importance of
pulsatile hormone release
• Demonstrated by GnRH infusion
• If given once hourly, gonadotropin secretion and
gonadal function are maintained normally
• A slower frequency won’t maintain gonad function
• Faster, or continuous infusion inhibits gonadotropin
secretion and blocks gonadal steroid production
Clinical correlate
• Long-acting GnRH analogs (such as leuproline)
have been applied to the treatment of
precocious puberty, to manipulate
reproductive cycles (used in IVF), for the
treatment of endometriosis, PCOS, uterine
leiomyoma etc
Endocrine Feedback Signals
• The strength of the feedback signal depends upon:
- the levels of hormone available
- the numbers of receptors for the hormone on the
target tissue
• The level of hormone available depends upon three
factors:
- rate of hormone production
- rate of hormone secretion
- rate of hormone clearance (breakdown, excretion)
Types of Factors Influencing Secretion Rates
• In general, there are 3 types of factors involved in the
regulation of secretion:
- neural
- endocrine
- humoral (glucose, osmolarity, blood pressure, etc.).
• The rate of hormone secretion can be regulated by
one or more types of factors.
e.g., Insulin secretion is stimulated by glucose levels,
parasympathetic nervous input, and gastric
hormones.
Neural Regulation of Hormone Secretion
• Secretion of hormones from cells can be
influenced by neuronal activity.
• Example: Release of norepinephrine and
epinephrine from the adrenal medulla.
stress
CNS
sympathetic nervous
system
Preganglionic
fibers
adrenal medulla
norepinephrine release
Neural Regulation of Hormone Release
• Another Example: Release of vasopressin from
the posterior pituitary
osmoreceptors
(supraoptic nucleus
of the hypothalamus)
posterior pituitary
vasopressin
Endocrine Control of Hormone Secretion
There are many examples in which a hormone is
secreted in response to another hormone.
• ACTH acts on the zona fasciculata to stimulate the
production of cortisol.
• LH acts on the Leydig cells to stimulate the
production of testosterone.
• Thyroid-Stimulating Hormone acts on the thyroid
to stimulate the release of T3, T4.
Neuroendocrine Regulation of Hormone
Release
• A number of releasing factors are secreted from the
hypothalamus, and travel to the anterior pituitary to
regulate hormone secretion. This is termed
neuroendocrine regulation (NOT neural regulation).
- GnRH: stimulates LH, FSH release
- CRF: stimulates ACTH release
- GHRH: stimulates GH release
- somatostatin: inhibits GH release
- TRH: stimulates TSH release
Feedback Control of Endocrine Secretion
Feedback control of Endocrine Secretion
Humoral Control of Secretion
• Hormones are also secreted in response to
changing levels of certain ions and nutrients.
• E.g., Parathyroid gland responds to decreased
Ca2+ levels with increased parathyroid hormone
release.
Humoral Control of Secretion
• Another example: aldosterone secretion
decreased [Na+],
increased [K+]
zona glomerulosa
aldosterone
Mechanisms of Regulated Release
• The effects described so far typically influence both
synthesis of hormone (last lecture) and release of
hormone.
• For steroid hormones, the rate of synthesis and rate of
production of a hormone are roughly the same (no
hormone storage).
 For peptide hormones, hormone can be
synthesized and stored in secretory vesicles
until there is a need for release.
Mechanisms of Release
• Peptide hormones are released from cells via
migration of secretory vesicles toward the cell
membrane. The vesicles fuse with the cell
membrane, releasing contents by exocytosis.
Regulated versus Constitutive Release
• Constitutive release: in many cells in the body, the
migration of vesicles to the cell surface is constant
and not regulated.
• Regulated release: in endocrine cells, the migration of
vesicles to the cell surface occurs when there is a
signal telling the cell to release hormone.
constitutive release
Receptor
regulated release
What are the postreceptor signals regulating
movement and release of vesicles?
• The detailed mechanisms are not well understood. May
involve movement along microtubules.
• Secretion is often dependent upon influx of calcium into
the cell.
- Influx of calcium results in cell depolarization.
- Cell depolarization is also sufficient to cause hormone
release.
- Calcium can act as a second messenger in cells, via
calmodulin (effects on enzyme activation via
phosphorylation)
-Calcium may influence microtubule contraction.
Influence of Second Messengers on Secretion
• In addition, there appears to be involvement of cyclic
AMP, at least in some cases (cAMP increases in response
to signal for release)
• Calcium may stimulate cAMP formation
• Example: Aplysia californica: California sea slug
- Secretes egg-laying hormone from bag cells
- Secretion is stimulated in cell culture by electical
depolarization of cells.
- Secretion can be inhibited by blockers of cAMPdependent protein kinase A
cyclic AMP
protein kinase A
phosphorylation of enzymes
Role of Protein Kinase A in Stimulated
Secretion of ELH
depolarizing
(+)
current
PKA inhibitor
Aplysia californica bag cells
(-)
ELH
causes egg-laying behavior in whole animals
Synthesis versus Secretion
• The signal pathways resulting in increased synthesis
of a peptide hormone may be different from the
signals causing increased release.
• Example: Actions of GnRH on LH synthesis and
release.
Calcium
GnRH
R
release
synthesis
Protein Kinase
C
LHb mRNA
Why Regulate Peptide Hormone Release?
• Allows for large, rapid changes in peptide hormone
levels.
• Allows for the release of peptide hormones at a
greater rate than the hormone is synthesized.
- peptide can be accumulated in secretory granules,
and rapidly released when necessary
Clearance of Hormone from the Body
• Since hormones are released in response to specific
conditions, they must be inactivated so they do not
continue to exert their effects for an indefinite period.
• Hormones are broken down, modified, and/or
removed from the blood and the body at different
rates.
• Hormones are excreted primarily from the kidney into
urine.
Endocrine Gland
Hormone
Target Cell
Action
Clearance Rates of Hormones
• The clearance rate of a hormone (how fast it is broken
down and/or removed from the blood) can be expressed
in two ways:
1) Metabolic Clearance Rate (MCR): the volume of blood
from which a hormone is completely removed in a given
period of time (ie, milliters/hour).
2) Circulating Half-life: The time it takes for 50% of a
hormone to be removed from the circulation.
Metabolic Clearance Rate
• The larger the MCR number, the faster the hormone is
removed from the blood.
• Example: a hormone with a MCR of 100 ml/minute is
removed faster than a hormone with a MCR of 50 ml/min.
• Theoretical calculation of clearance rate:
urine production x [concentration in urine]
(ml/min)
[concentration in plasma]
• However, hormones appear in urine after being metabolized,
and are thus difficult to measure.
Circulating Half-Life
Hormone
Concentration
• It is easier to determine the half-life of a hormone
(T1/2; how long it takes for 50% of the hormone to be
removed from the blood).
40
20
T1/2
0
0
10
20
30
Time (minutes)
40
Determining T1/2 of a Hormone
• BUT: Hormone is constantly made in the body. Thus, the rate
of decline depends upon not only clearance, but synthesis as
well.
• So, how is T1/2 calculated (answer given in lecture!).
Some Typical Half-lives of Hormones
Hormone
small peptides
T1/2
4-40 minutes
large proteins
(TSH, LH, FSH)
15 - 180 minutes
steroids
5 - 120 minutes
What Happens to Hormones During
Clearance?
• A very small amount of total circulating hormone is
degraded within cells by internalization following
binding to membrane receptors.
• Here’s what happens:
- peptide hormone binds to receptor on cell surface
- the hormone:receptor complex is internalized by
endocytosis to form a vesicle
- the vesicle may fuse with a lysosome, resulting in
degradation of the hormone
Ligand-Induced Internalization and
Degradation of Receptors and Hormones
H
receptor
H
H
lysozome
What Happens to Hormones During
Clearance?
• A very small amount (< 1%) of hormone is secreted in the
urine as intact hormone.
• The majority of peptide hormones and steroid hormones
are first metabolized (broken down or modified) before
secretion in the urine (mostly) and feces (< 10%).
• Most metabolism of hormones occurs in the liver and
kidneys.
What Happens to Hormones During
Clearance?
• Peptide hormones: enzymes cut between peptide
bonds in a specific manner
- endopeptidases cut within the peptide
- exopeptidases cut from each end (aminopeptidases
and carboxypeptidases)
- breaking disulfide bonds
endopeptidase
NH2
amino
acid 1
amino
acid 2
exopeptidase
amino
acid 3
amino
acid 4
exopeptidase
COOH
Metabolism of Steroid Hormones and
Thyroid Hormones
• A key step in the metabolism of steroid hormones by
the liver is the conjugation (adding on) of glucuronic
acid or sulfate groups.
• This conjugation makes the steroids more water
soluble (easier to excrete from the body).
• Conjugated steroids are excreted from the liver in
bile. They may then be reabsorbed into the blood
and excreted via kidneys into urine. Some is excreted
with bile in feces.
• Thyroid hormones (nonpeptide) are similarly
metabolized by the liver.
Factors Influencing the Half-life of Hormones
• There are three factors which appear to influence
the rate of clearance of hormones:
- size of the hormone (smaller peptides have
short half-lives)
- whether it binds to a binding protein (mostly
steroids)
- the glycosylation pattern
Influence of Binding Proteins on T1/2
• Many steroid hormones are found in the
circulation bound to carrier proteins (binding
proteins produced from the liver), due to their
insoluble nature.
• Bound hormone has a longer half-life (protected
from degradation).
• For example, most aldosterone is in the plasma in
free (not bound) form, and aldosterone has a very
short half-life.
Specificity of Binding Globulins
• Some binding proteins are highly specific, with high
binding affinity for their hormone:
-Testosterone Binding Globulin (TeBG; also called SHBG);
binds T and E2
- Cortisol Binding Globulin (CBG): binds cortisol
- Thyroid Hormone Binding Globulin (TBG): binds T3, T4
• Other proteins, such as albumin, bind a wider variety of
hormones, and bind less tightly
• While testosterone bound to albumin is biologically
available to tissues (loose binding), T bound to TeBG is
not biologically available.
Regulation of Binding Globulins
• The presence of carrier proteins influences half-life and
biological availability of steroid hormones.
• Interestingly, the production of these carrier proteins from
the liver is regulated in different physiological states.
• Example: During pregnancy, there is a stimulation of CBG
levels, DECREASING negative feedback of cortisol on ACTH
release.
ACTH release INCREASES, resulting in more cortisol
production, until the relative level of free/bound cortisol is
normal (restoration of negative feedback).
Why would you want this?
Regulation of CBG during Pregnancy
pregnancy
increased CBG
effects on fetal adrenal function?
decreased free cortisol
decreased negative feedback on ACTH normal free cortisol
increased ACTH release
increased cortisol release
Effects of Glycosylation on Half-life of Peptide
Hormones
• Some peptide hormones are glycosylated
(glycoproteins)
• There is a strong correlation between the amount
of sialic acid in the glycoprotein chains, and the
half-life of the hormone.
• Removal of sialic acid dramatically decreases the
half-life of the hormone.
Relationship Between Sialic Acid Content and
Glycoprotein Hormone Half-life
Hormone Half-life
LH
45 min
FSH
180 min
hCG
360 min
%Sialic Acid
2%
5
10
Glycosylation Pattern of LH, FSH, hCG
alpha subunit
FSH Beta
LH Beta
hCG Beta
Making “SuperFSH”
Using molecular techniques, one can add the
carboxyl terminus of hCGb onto FSHb, making an
FSH molecule with increased sialic acid content
(and increased half-life)
hCGb
FSHb
FSH+CTPb
Why Does Sialic Acid Matter?
• Sialic acid appears to protect the hormone from
metabolism by the kidney.
Is There Regulation of Sialic Acid Content of
Glycoproteins?
• Changes in sialic acid content have been reported
during aging in men and women (LH, FSH).
• Steroid hormones (testosterone and estradiol)
appear to influence sialic acid content.