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1. basic concepts of endocrine regulation
1. Basic Concepts of Endocrine
Regulation
Themba Hospital FCOG(SA) Part 1 Tutorials
By Dr N.E Manana
2. INTRODUCTION
• Endocrine physiology is concerned with the maintenance of various
aspects of homeostasis
• The mediators of such control mechanisms are soluble factors known
as hormones
• The word hormone was derived from the Greek horman, meaning to
set in motion.
• The endocrine system cannot be cleanly defined along anatomic lines
3. HORMONES AND THEIR ACTIONS
• Hormones comprise steroids, amines, and peptides
• Peptide hormones are by far the most numerous
• Among the peptide hormones, several are heterodimers that share a
common α chain, with specificity being conferred by the β-chain
• Steroids and thyroid hormones are distinguished by their
predominantly intracellular sites of action
4. HORMONE SYNTHESIS
• Regulation of hormone synthesis, of course, depends on their
chemical nature
• Peptide hormones as well as hormone receptors, synthesis is
controlled predominantly at the level of transcription
• Amine and steroid hormones, synthesis is controlled indirectly by
regulating the production of key synthetic enzymes
• In some cases, multiple hormones may be derived from the same
initial precursor
• Hormone precursors themselves are typically inactive
5. HORMONE SECRETION
• The secretion of many hormones is via a process of exocytosis of stored
granules
• However, contrast the secretion of stored hormones with that of those that
are continually released by diffusion (eg, steroids).
• Control of the secretion of the latter molecules occurs via kinetic influences
on the synthetic enzymes or carrier proteins involved in hormone
production
• Some hormones are secreted in a pulsatile fashion
6. HORMONE TRANSPORT
• 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
• Plasma carriers for specific hormones have a number of important
physiological functions
7. HORMONE ACTION
• Hormones exert a wide range of distinctive actions on a huge number
of target cells to effect changes in:
• Metabolism,
• Release of other hormones
• Regulatory substances, changes in ion channel activity,
• And cell growth, among others
• Ultimately, the concerted action of the hormones of the body ensures
the maintenance of homeostasis.
10. HORMONE RESISTANCE
• Many of the consequences of hormone deficiency can by reproduced
in disease states where adequate levels of a given hormone are
synthesized and released, but the target tissues become resistant
• There is often overproduction of the implicated hormone in these
conditions because the feedback loops that normally serve to shut off
hormone synthesis and/or secretion are similarly desensitized
• Mutations in hormone receptors (especially nuclear receptors) may
result in heritable syndromes of hormone resistance.
• Functional hormone resistance that develops over time is also seen
11. HORMONE EXCESS
• The converse of disorders of hormone deficiency or resistance is seen
in diseases associated with hormone excess and/ or over-stimulation
of hormone receptors
• A wide variety of endocrine tumors may produce hormones in an
excessive and uncontrolled fashion
• In addition, other endocrine tumors may secrete hormones other
than those characteristic of the cell type or tissue from which they are
originally derived
• Disorders of hormone excess can also be mimicked by antibodies that
bind to, and activate, the receptor for the hormone
Rather, the endocrine system is a distributed system of glands and circulating messengers that is often stimulated by the central nervous system and/or autonomic nervous system
In the specific case of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), there is evidence that the distinctive β-chains arose from a series of duplications of a common ancestral gene
The underlying ancestral relationships sometimes re-emerge, however, in the cross-reactivity that may be seen when hormones rise to unusually high levels (eg, endocrine tumors)
They bind to a family of largely cytoplasmic proteins known as nuclear receptors
Interestingly, the majority of peptide hormones are synthesized initially as much larger polypeptide chains, and then processed intracellularly by specific proteases to yield the final hormone molecule
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,
These effects are mediated by the ability of glucose to increase the interaction of the insulin mRNA with specific RNA binding proteins, which increase its stability and enhance its translation.
The net effect is a more precise and timely regulation of insulin levels, and thus energy metabolism, than could be accomplished with
The precursors for peptide hormones are processed through the cellular machinery that handles proteins destined for export, including trafficking through specific vesicles where the propeptide form can be cleaved to the final 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.
transcriptional regulation alone.
Pulsatile secretion is often related to the activity of oscillators in the hypothalamus that regulate the membrane potential of neurons
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.
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 phosphatases. StAR traffics cholesterol from the outer to the inner membrane leaflet of the mitochondrion.
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
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
Catecholamine and most peptide hormones are soluble in plasma and are transported as such. In contrast steroid hormones are hydrophobic and are mostly bound to large proteins called steroid binding proteins (SBP)
Plasma carriers for specific hormones have a number of important physiological functions.
First, they serve as a reservoir of inactive hormone and thus provide a hormonal reserve. Bound hormones are typically prevented from degradation or uptake.
Thus, the bound hormone reservoir can allow fluctuations in hormonal levels to be smoothed over time.
Plasma carriers also restrict the access of the hormone to some sites. Ultimately, plasma carriers may be vital in modulating levels of the free hormone in question.
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 steroid binding proteins (SBP), which are synthesized in the liver.
As a result, only small amounts of the free hormone are dissolved in the plasma. Specifically, sex hormone-binding globulin (SHBG) is a glycoprotein that binds to the sex hormones,
In a pathophysiological setting, some medications can alter levels of binding proteins or displace hormones that are bound to them.
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 testosterone and 17β-estradiol. Progesterone, cortisol, and other corticosteroids are bound by transcortin
However, a subset of the hormones, as detailed in Table 16–1 , are the key contributors to homeostasis.
These include thyroid hormone, cortisol, parathyroid hormone, vasopressin, the mineralocorticoids, and insulin.
Hydrophilic hormones, including peptides and catecholamines, exert their acute effects by binding to cell surface receptors
Hydrophobic hormones, in the other hand, predominantly exert their actions via nuclear receptors. Th ere are two classes of nuclear receptors that are important in endocrine physiology.
The first of these provide for direct stimulation of transcription via induction of the binding of a transcriptional co-activator when the hormonal ligand is bound.
In the second class, hormone binding triggers simultaneous dislodging of a transcriptional co-repressor and recruitment of a co-activator
These extranuclear receptors, some of which may be structurally related or even identical to the more classical nuclear receptors, are proposed to mediate rapid responses to steroids and other hormones that do not require alterations in gene transcription.
The physiological effects at these receptors may therefore be distinct from those classically associated with a given hormone.
Evidence is accumulating, for example, that plasma membrane receptors for estrogen can mediate acute arterial vasodilation as well as reducing cardiac hypertrophy in pathophysiological settings
the responsiveness of target cells to hormonal action subsequently “feeds back” to control the inciting endocrine organ.
Feedback can regulate the further release of the hormone in either a negative feedback or (more rarely) a positive feedback loop
Positive feedback relates to the enhancement or continued stimulation TABLE 161 Major hormonal contributors to homeostasis. Hormone Source Action Thyroid hormone Thyroid Controls basal metabolism in most tissues Cortisol Adrenal cortex Energy metabolism; permissive action for other hormones Mineralocorticoids Adrenal cortex Regulate plasma volume via eff ects on serum electrolytes Vasopressin Posterior pituitary Regulates plasma osmolality via eff ects on water excretion Parathyroid hormone Parathyroids Regulates calcium and phosphorus levels Insulin Pancreas Regulates plasma glucose concentration + + Adrenal Gonads Thyroid Hypothalamus CNS Releasing factors Pituitary Trophic hormones Target hormone feedback inhibition FIGURE 163 Summary of feedback loops regulating endocrine axes. CNS, central nervous system. (Reproduced with permission from Jameson JL (editor): Harrison’s Endocrinology 2nd ed. McGraw Hill, 2010. ) of the original release mechanism/stimulus. Such mechanisms are really only
Negative feedback is a far more common control mechanism and involves the inhibition or dampening of the initial hormone release mechanism/stimulus
seen in settings that need to gather momentum to an eventual outcome, such as parturition
Resistance arises from a relative failure of receptor signaling to couple efficiently to downstream intracellular effector pathways that normally mediate the effects of the hormone
Target tissues for insulin gradually become more and more resistant to its actions, secondary to reduced activation of phosphatidylinositol 3-kinase and other intracellular signaling pathways.
A key factor precipitating this outcome is obesity.
In addition, because of excessive insulin secretion, pancreatic β cells become “exhausted” and may eventually fail, necessitating treatment with exogenous insulin.
Note that the secretion of hormones from tumor cells may not be subject to the same types of feedback regulation that are seen for the normal source of that hormone
In the setting of an endocrine tumor, exaggerated effects of the hormone are seen
