Endocrine System: Hormones and Homeostasis

Endocrine Physiology Overview

• Concerned with maintaining homeostasis
• Mediated by soluble factors called hormones
• "Hormone" derives from the Greek word "horman," meaning to set in motion

Endocrine System Characteristics

• Cannot be distinctly defined based on anatomical boundaries
• Operates as a distributed network
• Comprises glands and circulating messengers
• Influenced by the central nervous system, autonomic nervous system, or both.

Hormone Composition

• Consists of steroids, amines, and peptides
• Peptide hormones are the most numerous
• Many hormones are grouped into families reflecting their structural similarities and the similarity of receptors they activate
• Hormone diversity increases from simple to higher life forms, reflecting challenges in providing homeostasis in complex organisms
• Evidence indicates the distinctive β-chains of TSH, FSH, and LH arose from duplications of an ancestral gene
• Hormone receptors also evolved to allow for the spreading of hormone actions/specificity via co-evolution of GPCRs and receptor tyrosine kinases that mediate peptide and amine hormone effects at the cell surface

Steroid and Thyroid Hormones

• Distinguished by their intracellular sites of action
• Diffuse freely through the cell membrane, binding to nuclear receptors in the cytoplasm
• The receptor-ligand complex translocates to the nucleus, where it either homodimerizes or associates with another receptor to form a heterodimer
• The dimer binds to DNA to increase or decrease gene transcription

Peptide Hormone Examples

• TSH, FSH, and LH are heterodimers sharing an alpha chain, with specificity conferred by the beta chain
• Beta chains evolved from gene duplication of a common ancestor
• This evolution necessitated hormonal receptor evolution for hormone action spreading and specificity, via GPCRs and tyrosine kinase receptors, which mediate peptide and amine hormones at the cell surface.

Hormone Synthesis Regulation

• Depends on chemical nature
• Peptide hormones: controlled primarily at the level of gene transcription, as well as hormone receptors
• Amine and steroid hormones: controlled indirectly by regulating the production of key synthetic enzymes and substrate availability
• Interestingly, a large number of peptide hormones are synthesized as larger polypeptide chains, then processed intracellularly by specific proteases to yield the final hormone molecule
• In some cases, multiple hormones may be derived from the same initial precursor which enables genetic "economy"
• Hormone precursors themselves are typically inactive to provide an additional regulatory control measure
• Thyroid hormones: dictate the site of highest hormone availability

Hormone Secretion

• Many hormones are secreted via exocytosis of stored granules
• This process is activated when the cell type that synthesizes and stores the hormone is activated by a specific signal, such as a neurotransmitter or peptide-releasing factor
• Secretion contrasts with the continuous release of hormones via diffusion (e.g., steroids)

Control of Secretion of Molecule (Steroids)

• Occurs via kinetic influences on the synthetic enzymes or carrier proteins involved in hormone production
• Steroidogenic acute regulatory protein (StAR) is an unstable protein whose expression, activation, and deactivation are regulated by intracellular signaling cascades
• StAR traffics cholesterol from the outer to the inner membrane leaflet of the mitochondrion
• This is a rate-limiting first step in the synthesis of the steroid precursor, pregnenolone, enabling changes in the rate of steroid synthesis in response to cues like trophic hormones, cytokines, and stress

Secretion Mechanisms in Comparison

• Stored hormones are secreted in response to specific signals that induce exocytosis
• Other hormones, like steroids, are released through continuous diffusion across cell membranes

Pulsatile Secretion of Hormones

• Some hormones are secreted in this manner, with secretion rates peaking and ebbing (oscillatory or intermittent patterns)
• This is relative to circadian rhythms, meal timing, or other pattern generators (milliseconds to years)
• Linked to hypothalamic oscillators regulating neuron membrane potential and hormone-releasing factor bursts into hypophysial blood flow
• Impacts hormone influence on target tissues
• It may be challenging therapeutically to replace hormones secreted in a pulsatile manner due to deficiency

Factors Influencing Circulating Hormone Levels

• The rate of secretion and its nature (steady vs. pulsatile)
• Rates of hormone degradation and/or uptake
• Receptor binding and availability
• Affinity for plasma carriers
• Stability influences the circulating half-life of a given hormone, with therapeutic implications for hormone replacement therapy

Plasma Carriers Functions

• Serve as a reservoir of inactive hormones
• Prevent degradation or uptake of bound hormones
• Allow fluctuations in hormonal levels to be smoothed over
• Restrict hormone access to some sites
• Modulate levels of the free hormone

Free Hormones

• The only biologically active form in tissues
• It is what mediates feedback regulation since it can access the extravascular compartment
• Steroid hormones are hydrophobic and mostly bound to steroid-binding proteins (SBPs) that are synthesized in the liver
• Only small amounts of free hormones are dissolved in the plasma

Examples of Hormones Carriers

• Sex hormone-binding globulin (SHBG) (glycoprotein) binds to sex hormones, testosterone, and 17β-estradiol
• Transcortin binds to progesterone, cortisol, and other corticosteroids

Regulation of Protein Carriers

• Regulating the expression and secretion of the carrier proteins, such as steroids, is key to regulating the availability of hormones

Hormone Action and Effects

• Wide range of distinctive actions on target cells
• Effects include: changes in metabolism, the release of hormones and regulatory substances, changes in ion channel activity, and cell growth
• Concerted action ensures the maintenance of homeostasis
• All hormones affect homeostasis to some degree; key contributors include thyroid hormone, cortisol, parathyroid hormone, vasopressin, mineralocorticoids, and insulin

Types of Hormone Binding

• Hydrophilic hormones bind to receptors on the cell surface, typically GPCRs
• Hydrophobic hormones exert actions via nuclear receptors

Principles of Feedback Control

• Target cells' responsiveness "feeds back" to control the inciting endocrine organ
• Feedback regulates hormone release via negative or positive feedback loops

Positive Feedback

• Relates to the enhancement or continued stimulation of the original release mechanism/stimulus
• Seen in settings requiring momentum for an eventual outcome (e.g., parturition)

Negative Feedback

• It is a far more common control mechanism that causes the inhibition or dampening of the initial hormone release mechanism/stimulus

Endocrine System Responses

• The endocrine system uses a range of feedback responses to maintain a steady state
• Negative feedback control systems are the most common feedback/homeostatic systems
• Feedback control loops serve diagnostic strategies in suspected endocrine disorder evaluations