Basic Concempts of Endocrine Regulation

Prof. N.
SYABBALO
MB., ChB., PhD., FCCP., FRS., FIBA
Professor of Physiology & Medicine

BASIC CONCEPTS OF ENDOCRINE
REGULATION
The unique feature of endocrine physiology is that,
unlike other physiological systems, the endocrine
system cannot be defined along anatomic lines
Rather, the endocrine system is a distributed system of
glands and circulating messengers (hormones) that is
often simulated by the central nervous system and/or
autonomic nervous system
Hormones comprise steroids, amines, and peptides
Peptides are by far the most numerous
BASIC CONCEPTS OF ENDOCRINE
REGULATION
They include hormones secreted by the anterior and
posterior pituitary gland, the pancreas (insulin and
glucagon), the parathyroid gland (parathyroid hormone)
and many others
Steroids are secreted by the adrenal cortex (cortisol and
aldosterone), the ovaries (estrogen and progesterone), the
testes (testosterone), and the placenta (estrogen and
progesterone)
Derivatives of the amino acid tyrosine are secreted by the
thyroid gland (thyroxine and triodothyronine), and the
adrenal medulla (epinephrine and norepinephrine)
EVOLUTION OF HORMONES AND
THEIR ACTIONS ON TARGET CELLS
Many hormones can be grouped into families
reflecting their structural similarities as well as the
similarities of the receptors they activate
However, the number of hormones and their diversity
increase as one moves from simple to higher life forms
This reflects the added challenges in providing for
homeostasis in more complex organisms
For example, among the peptides hormones, several
are heterodimers that share a common σ chain, with
specificity being conferred by the chain
In the specific cases of thyroid-stimulating hormone
(TSH), follicular-stimulating hormone (FSH), and
luteinizing hormone (LH), there is evidence that the
distinct chains arose from a series of duplications of a
common ancestral gene
For these and other hormones, moreover, this
molecular evolution implies that hormone receptors
also needed to evolve to allow for spreading of
hormone actions/specificity
This was accomplished by co-evolution of the basic G-
protein coupled receptors (GPCR) and receptor
tyrosine kinases that mediate the effects of peptide and
amine hormones that act on the cell surface
The underling ancestral relationship sometimes re-
emerge, however, in the cross-reactivity that may be seen
when hormones rise to unusually high levels (eg,
endocrine tumours)
Steroids and thyroid hormones are distinguished by their
predominantly intracellular sites of actions, since they
can diffuse freely through the cell membranes
They bind to a largely cytoplasmic proteins known as
nuclear receptors
Upon ligand binding, the receptor-ligand complex
translocates to the nucleus where it either
homodimerizes, or associates with a distinct liganded
nuclear receptor to form a heterodimer
In either case, the dimer bind to DNA to either increase
or decrease gene transcription in the target tissue
Individual members of the nuclear receptor family have
a considerable degree of homology
This, perhaps implying a common ancestral gene, and
share many functional domains, such as the zinc
fingers that permit DNA binding
However, sequence variations allow for ligand
specificity as well as binding to specific DNA motifs
In this way, the transcription of distinct genes is
regulated by individual hormones
HORMONE SECRETION
SYNTHESIS AND PROCESSING
The regulation of hormone synthesis, depends on
their chemical nature
Polypeptides and protein hormones
The synthesis of all of the protein/peptide hormones
as well as hormone receptors, is subject to a normal
mechanisms of transcriptional control in the cell
In addition, there is provision for exquisitely specific
regulation by other hormones, since the regulatory
regions of many peptide hormone genes contain
binding motifs for nuclear receptors
HORMONE SECRETION
Peptide are synthesized on the rough end of the
endoplasmic reticulum of different endocrine cells in
the same fashion as most other proteins
They are usually synthesized at first as larger proteins
that are not biologically active (preprohormones)
and are cleaved to form smaller prohormones in the
endoplasmic reticulum by specific proteases
In some cases, multiple hormones may be derived
from the same initial precursor, depending on the
specific processing steps present in a given cell
HORMONE SECRETION
Presumably this provides for a form of genetic
‘economy’
Prohormones are then transferred to the Golgi
apparatus for packaging into secretory vesicles
In this process, enzymes in the vesicles leave the
prohormones to produce smaller, biologically active
hormones and inactive fragments
The vesicles are stored within the cytoplasm, and
many are bound to the cell membranes until their
secretion is needed
HORMONE SECRETION
Secretion of the hormone occurs when the secretory
vesicles fuse with the cell membrane and the granular
contents are extruded into the interstitial fluid or directly
into blood stream by exocytosis
The stimulus for exocytosis is an increase in cystolic
calcium concentration caused by depolarization of the
plasma membrane
In other instances, stimulation of endocrine cell surface
receptor causes increased cyclic adenosine
monophosphate (cAMP) and subsequently activation of
protein kinase that initiate secretion of the hormone
HORMONE SECRETION
The peptide hormones are water soluble, allowing
them to enter the circulation system easily, where they
are carried to their target tissues
Steroid hormones
For steroid hormones, synthesis is controlled
indirectly by regulating the production of key
synthetic enzymes, as well as by substrate availability
The chemical structure of steroid hormones is similar
to that of cholesterol, and in most instances they are
synthesized from cholesterol itself
HORMONE SECRETION
They are lipid soluble and consist of three cyclohexyl
rings and one cyclopentyl ring combined into a single
structure
Although there is usually very little hormone storage
in steroid-producing endocrine cells, large amount of
cholesterol ester in cytoplasm vacuoles can be rapidly
mobilized for steroid synthesis after a stimulus
Most of the cholesterol in steroid-producing cells
comes from the plasma, but there is also de novo
synthesis of cholesterol in steroid-producing cells
HORMONE SECRETION
Because the steroids are highly lipid soluble, once they
are synthesized, they simply diffuse across the cell
membrane and enter the interstitial fluid and then the
blood
Amine hormones
The two groups of hormones derived from tyrosine,
the thyroid and the adrenal medullary hormones are
formed by the actions of enzymes in the cytoplasmic
compartments of the glandular cells
HORMONE SECRETION
The thyroid hormones are synthesized and stored in the
thyroid gland and incorporated into macromolecules of
the protein thyroglobulin which is stored in large
follicles within the thyroid gland
Hormone secretion occurs when the amines are split
from thyroglobulin, and the free hormones (T 3 and T4)
are released into the blood stream
After entering the blood, most of the thyroid hormones
combine with plasma proteins, especially thyroxine-
biding globulin, which slowly release the hormones to
the target tissues
HORMONE SECRETION
Epinephrine and norepinephrine are formed in the
adrenal medulla, which secretes about four times more
epinephrine than norepinephrine
Catecholamines are stored in preformed vesicles and
stored until secreted
Similar to the protein hormones, catecholamines are
also released from adrenal medullary cells by exocytosis
Once they enter the circulation, they can exist in plasma
in free form or in conjugation with other substances
HORMONE SECRETION
Most importantly is that, hormone precursors
themselves are typically inactive
This may be a mechanism that provides for an
additional measure of regulatory control, or, in the
case of thyroid hormones, may dictate the site of
highest hormone availability
In addition, there is provision for exquisitely specific
regulation by other hormones, since the regulatory
regions of many peptide hormone genes contain
binding motifs for nuclear receptors
HORMONE SECRETION
For example, thyroid hormone directly suppresses
TSH expression via the thyroid hormone receptor
These specific mechanisms to regulate hormone
transcription are essential to the function of feedback
loops
In some cases, the abundance of selected hormones
may also be regulated via effects on translation
For example, elevated levels of circulating glucose
stimulate the translation of insulin mRNA
HORMONE SECRETION
These effects are mediated by the ability of glucose to
increase the interaction of insulin mRNA with specific
RNA binding proteins, which increase its stability and
enhances its translation
The net effect is a more precise and timely regulation
of insulin levels, and thus energy metabolism, than
could be accomplished with transcriptional regulation
alone
HORMONE SECRETION
The precursor for peptide hormones are processed
through the cellular machinery that handles proteins
destined for export, including trafficking through special
vesicles where the propeptide form can be cleaved to the
active hormones
Mature hormones are also subjected to a variety of
posttranslational processing steps, such as glycosylation,
which can influence their ultimate biological activity
and/or stability in the circulation
Ultimately, all hormones enter either the constitutive or
regulated secretory pathway
SECRETION
The secretion of many hormones is via a process of
exocytosis of stored granules
The exocytotic machinery is activated when the cell
type that synthesizes and stores the hormone in
question is activated by a specific signal, such as a
neurotransmitter or peptide releasing factor
One should, however, contrast the secretion of stored
hormones with that of those that are continuously
released by diffusion (eg, steroids)
SECRETION
Control of secretion of the later molecule occurs via
kinetic influence on synthetic enzymes or carrier
proteins involved in the hormone production
For example, the steroidogenic acute regulatory
protein (StAR) is a labile protein whose expression,
activation, and deactivation are regulated by
intracellular signaling cascades and their effectors,
including a variety of protein kinases and phosphates
StAR traffics cholesterol form the outer to the inner
membrane leaflet of the mitochondrion
SECRETION
Because this is a rate-limiting first step in the
synthesis of the steroid precursor, pregnenolone, this
arrangement permits changes in the rate of steroid
synthesis, and thus secretion, in response to
homeostatic cues such as trophic hormones, cytokines
and stress (Figure 16-1)
An additional complexity related to hormone
secretion relates to the fact that some hormones are
secreted in a pulsatile fashion
SECRETION
Pulsatile secretion is the normal pattern for the
gonadotrophins, LH and FSH, with major pulses
released every 1-2 hours depending on the phase of the
menstrual cycle
Growth hormone is also secreted in pulsatile fashion,
with undetectable levels between pulses
Secretion rates may peak and ebb relative to circadian
rhythms, in response to the timing of meals, or as
regulated by other pattern generators whose
periodicity may range from milliseconds to years
SECRETION
Circadian means changes over 24 hours of the day-
night cycle and is best shown by the pituitary-adrenal
axis
For example, cortisol levels are highest in the morning
and lowest in overnight
Additionally, cortisol release is pulsatile, following the
pulsatility of pituitary ACTH
The menstrual cycle is an example of a longer and
more complex (28-day biological rhythm)
SECRETION
Pulsatile secretion is often related to the activity of
oscillators in the hypothalamus that regulate the
membrane potential of neurons
Which in turn secret bursts of hormone releasing factors
into the hypophysial blood flow that then cause the
release of pituitary and other downstream hormones in a
pulsatile fashion
There is evidence that these hormones pulses convey
different information to the target tissues that they act
upon than steady exposure to a single concentration of
the hormone
SECRETION
Therapeutically, pulsatile secretion may pose
challenges if, due to deficiency, it proves necessary to
replace a pulsatile hormone that is normally secreted
in this way
Continuous secretion is typical of thyroid
hormones, with a half-life of 7-1o days for T4 and 6-10
hours for T3, and with little variation over the day,
month and year
FIGURE 16-1
Regulation of steroid biosynthesis by StAR
Extracellular signals activate intracellular kinases that,
in turn, phosphorylate transcription factors that
upregulate StAR expression
StAR is activated by phosphorylation, and facilitates
transfer of cholesterol from the outer to inner
mitochondrial membrane leaflet
This then allows entry of cholesterol into the steroid
biosynthetic pathway, beginning with pregnenolone
HORMONE TRANSPORT IN BLOOD
In addition to the rate of secretion and its nature (steady
vs pulsatile), a number of factors influence the circulating
levels of hormones
These include the rates of hormone degradation and/or
uptake
Receptor binding and availability of receptors, and the
affinity of a given hormone for plasma carriers
Stability influences the circulating half-life of a given
hormone and has therapeutic implications for hormone
replacement therapy, in addition to those posed by
pulsatile secretion
Plasma carriers for specific hormones have a number
of important physiological function
First, they serve as a reservoir of inactive hormone and
thus provide a hormonal reserve
Bound hormones are typically prevented from
degradation or uptake
Ultimately, plasma carriers may be vital in modulating
levels of the free hormones
Typically, it is only the free hormone that is
biologically active in target tissues or can mediate
feedback regulation since it is the only form able to
access the extravascular compartment
Thus, the bound hormone reservoir can allow
fluctuation in hormonal levels to be smoothed over
time
Plasma carriers also restrict the access of the hormone
to some sites
Catecholamines and most peptide hormones are
soluble in plasma and are transported as such
Norepinephrine and epinephrine, are secreted within
seconds after the gland is stimulated, and they may
develop full action within another few seconds to
minutes
In contrast steroid hormones are hydrophobic and are
mostly bound to large proteins called steroid binding
proteins (SBP), which are synthesized in the liver
As a result, only small amounts of the free hormone
are dissolved in plasma
Specifically, sex hormone-binding globulin (SHBG)
is a glycoprotein that binds to the sex hormones,
testosterone and 17β-estradiol
Progesterone, cortisol, and other corticosteroids are
bound by transcortin
The SBP hormone complex and the free hormone are
in equilibrium in the plasma, and only the free
hormone is able to diffuse across cell membranes
SBP have three main functions: they increase the
solubility of lipid based hormone in the blood
They reduce the rate of hormone loss in the urine by
preventing the hormone from being filtered in the
kidney
And they provide a source of hormone in the
bloodstream that can release free hormone as the
equilibrium change
An additional way to regulate the availability of hormones
that bind to a carrier proteins, such as steroids, is to
regulate the expression and secretion of the carrier
proteins themselves
This is a critical mechanism that regulates the
bioavailability of thyroid hormones, for example
Thyroid hormones are transported in the circulation by a
carrier protein thyroxine-binding globulin
In a pathophysiological setting, some medications can
alter the levels of binding proteins or displace hormones
that are bound to them
This is a critical mechanism that regulates the
bioavailability of thyroid hormones, for example
In addition, some binding proteins are promiscuous and
bind multiple hormones (eg, SHBG)
These observations may have clinical implications for
endocrine homeostasis, since free hormones are needed
to feedback and control their rates of synthesis and
secretion
Finally, the anatomic relationship of sites of release and
action of hormones may play a key role in their regulation
For example, a number of hormones are destroyed by
passage through the pulmonary circulation or the liver
This may markedly curtail the temporal window within
which a given hormone can act
Concentration of hormones in the circulation
The concentration of hormones required to control most
metabolic and endocrine functions are incredibly small
Their concentration in the blood range from as little as 1
picogram in each millilitre of blood up to at most a few
milligrams per millimetre of blood
Similarly, the rates of secretion of various hormones
are extremely small, measured in micrograms or
milligrams per day
The rate of action of hormones also varies
Norepinephrine and epinephrine may develop full
action within seconds to minutes after being secreted,
the actions of other hormones, such as thyroxine or
growth hormones, may require months for full effect
CLINICAL BOX 16-1
Breast cancer
Breast cancer is the most common malignancy of
women, with about 1 million new cases diagnosed each
year world-wide
The proliferation of more than two-thirds of breast
tumours are driven by the ovarian hormone, oestrogen,
and about one-third of patients, the breast cancer will
express receptors for oestrogen and progesterone
This is by virtue of the fact that the tumour cells express
high levels of posttranslationally modified oestrogen
receptors (ER)
CLINICAL BOX 16-1
Breast cancer
The clinical significance of these molecular findings
has been known for more than 100 years, since the
Scottish surgeon, Sir Thomas Beatson, reported
delayed disease progression in patients with advanced
breast cancer following removal of their ovaries in
premenopausal women
The extent of exposure to ovulatory cycles is one of
most important endogenous causes associated with a
high risk for development of sporadic breast cancer
CLINICAL BOX 16-1
Breast cancer
However, although the association of oestrogen in the
development of breast cancer is well established, the
fundamental mechanism(s) by which this hormone
modulate cell growth and tumour development are not
yet clear
It is known from in vitro and in vivo studies that the
mechanism of oestrogen action is mediated through
the binding to the ER
Oestrogen receptors in turn binds specific enhancer
regions on the DNA and regulates gene transcription
CLINICAL BOX 16-1
Breast cancer
The interaction of oestrogen and its receptors and the
recruitment of accessory cofactor proteins has been
the focus of intense recent research
In modern times, determination of whether a given
breast cancer is, or is not, ER-positive is a critical
diagnostic test that guides treatment decisions, as well
as an important prognosticator
ER-positive tumours are typically of lower grade, and
patients with such tumours have improved survival
CLINICAL BOX 16-1
Breast cancer
The latter is likely due, at least in part, to the
availability of excellent treatment options for ER-
positive tumours compared with those that are ER-
negative
On the other hand, the oestrogen receptor negative,
progesterone receptor (R) negative, mutated EGFR
(Her2) negative, triple negative phenotype (basal type)
is associated with a poor prognosis than the luminal
types A and B
THERAPEUTIC HIGHLIGHTS
Oestrogen-responsive breast tumours are dependent
on the presence of the hormone for growth
In modern times, cells can be deprived of the effects of
oestrogen pharmacologically, rather than resorting to
oophorectomy
Premenopausal women
In premenopausal women, a reduction in oestrogens
can be achieved via pituitary downregulation using
gonadotropin-releasing hormone (GnRH) analogues
such as goserelin or leuprorelin
Tamoxifen a mixed agonist and antagonist of oestrogen
action on the ER, and related agents that specifically
inhibit the oestrogen receptor may hasten its degradation
The more recent drug fulvestrant is a more selective
oestrogen modulator (SERM) and is also used for the
treatment of breast cancer
Synthetic progestogens, eg, medroxyrogesterone acetate
and megestrol, have a direct effect on breast tumour cells
through progesterone receptors
They can be as effective as tamoxifen in metastatic breast
cancer
Postmenopausal women
In postmenopausal women, where oestrogen is
derived from the metabolism of testosterone to
estrone in extragonadal tissues (ie, subcutaneous fat)
rather than from the ovaries, aromatase inhibitors
inhibits the conversion of androgens to oestrogen
The aromatase inhibitors, anastrozole, letrozole
and exemestane, reduce circulating oestrogen levels
and synthesis in tumour cells
They have shown greater efficacy than tamoxifen in the
treatment of metastatic breast cancer and equivalent in
adjuvant setting
In general, treatment of breast cancer includes surgery:
local excission, segmental mastectomy or simple
mastectomy with or without reconstruction, radiation
therapy, chemotherapy and hormone-modulating
therapy, e.g., taxomifen
Patients with established metastatic disease may require
endocrine therapy, chemotherapy and radiotherapy
The anti-oestrogen drug taxomifen is effective when
used as a single agent or when used in combination
with other chemotherapeutic agents in patients who
are postmenopausal
Chemotherapy is used for patients who lack features
of hormone responsive disease or who fail to respond
to endocrine therapy or who require rapid response if
at risk of, eg, liver or respiratory failure
There is no advantage in combining more than two
drugs at a time
There is very little difference in efficacy between the different
regimens for metastatic disease, with response rates varying
from 40% to 60% for median duration of 8-10 months
The most common regimens with either single agent or
doublet combination include:
MM: mitoxantrone and methotraxate
AC/EC: doxorubicin or epirubicin and cyclophosphamide
DC: docetaxel and gemcitabine
PG: paclitaxel and gemcitabine
Vinorelbine, carbolatin, mitomycin and eribulin

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Prof. N.

Professor of Physiology & Medicine

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