Principles of Endocrinology and Hormone Action

Marco Infante, MD, PhD, FACN

Adjunct Professor of Endocrinology and Applied Nutrition in Internal Medicine

UniCamillus, Saint Camillus International University of Health Sciences, Rome

Email: [email protected]
 Definition and Scope of Endocrinology
 Endocrinology is the branch of biology and medicine concerned with the endocrine system, its diseases

and the secretory products of endocrine glands known as “hormones”

 Endocrine glands are ductless glands of the endocrine system which synthesize and secrete hormones

directly into the blood

 Hormones (from the Greek verb hormao, “to set in motion") are signaling molecules, produced by

endocrine glands, that are transported through the bloodstream (often bound to a plasma protein) to target

distant organs and tissues/cells to regulate their physiology and behavior (endocrine effect)

 Hormones can also act locally following secretion, either on a neighboring cell (paracrine effect), or on the

secretory cell itself (autocrine effect)

Intercellular communication by
chemical mediators
(a) Autocrine

(b)

Greenspan’s, 10th Edition

 Exocrine glands vs. Endocrine glands

Exocrine glands secrete Endocrine glands are

substances through ducts ductless glands that
onto an epithelial surface secrete hormones directly
into the bloodstream
Examples:
Examples:
Salivary glands
Thyroid gland
Breast
Adrenal glands
Exocrine pancreas
Endocrine pancreas
The Endocrine System
 Examples of organs with secondary endocrine functions
Organ Examples of hormones produced by
different endocrine cells
Heart Natriuretic polypeptide hormones produced by atrial cardiomyocytes:
• Atrial natriuretic factor, a.k.a. Atrial natriuretic peptide (ANF or ANP)
• Brain natriuretic peptide (BNP)
Gastrointestinal tract • Gastrin (G cells – gastric antrum and duodenum)
[Gastro-entero-pancreatic (GEP) endocrine system] • Ghrelin (P/D1 cells – gastric fundus)
• Cholecystokinin (CCK) (I cells – proximal small intestine)
• Somatostatin (D cells – gastric corpus and antrum, small intestine)
• Glucose-dependent insulinotropic polypeptide (GIP) (K cells – proximal small intestine)
• Glucagon-like peptide 1 (GLP-1), GLP-2, peptide YY (PYY) (L cells – distal small intestine,
colon)
• Serotonin [5-hydroxytryptamine (5-HT)] [enterochromaffin (EC) cells, a.k.a. as Kulchitsky
cells – stomach, small and large intestine]
Kidneys • Renin – Juxtaglomerular cells (JGCs)
• Calcitriol [a.k.a. 1,25(OH)2D], which is hydroxylated by the enzyme 1α-hydroxylase
(CYP27B1) located in the mitochondria of proximal tubules of the kidney
• Erythropoietin (EPO) – Renal cortex peritubular cells
Adipose tissue • Adipose-derived hormones and adipokines (e.g., leptin, adiponectin, resistin, visfatin, etc.)

Thymus • Thymosin (thymosin-producing cells of the thymus)

Diffuse endocrine system (DES) DES is composed of neuroendocrine cells scattered throughout the entire body, either isolated
or grouped to form discrete aggregates, such as the neuroepithelial bodies in the
bronchopulmonary tract.
 Chemical Nature of Hormones
 Large proteins, polypeptides and glycoproteins (e.g., insulin, ACTH, GH, PRL,

PTH; glycoproteins: FSH, LH, TSH)

 Small neuropeptides (e.g., GnRH, TRH, ADH, somatostatin)

 Amino acid derivatives (thyroid hormones, catecholamines, dopamine)

 Steroid hormones (e.g., cortisol, estrogen, testosterone, progesterone)

 Vitamin derivatives (e.g., vitamin A, vitamin D)

Principles of Hormone Action

1. Hormone biosynthesis and secretion

2. Feedback regulation

3. Hormone transport

4. Hormone-receptor binding

5. Initiation of intracellular signaling

 Hormone biosynthesis and release
Protein or peptide hormones
• Increased expression of genes encoding the hormone leads to subsequent increases in hormone synthesis.

• Peptides, proteins, and monoamines are generally stored in secretory granules in endocrine cells.

• Release of these granules is promoted by signaling events triggered by exogenous regulators termed
“secretagogues”.

Steroid or thyroid hormones

• Increased sequestration of precursors for hormone synthesis (e.g., cholesterol for steroid hormones or
iodide for thyroid hormones) and increased activity of enzymes responsible for executing the individual
catalytic events required for hormone production.

• Steroid hormones are not stored in secretory granules to a significant degree in the hormone-producing cells;
steroid hormones usually diffuse into the bloodstream as they are synthesized.
 Precursor processing: examples
a) Pancreas b) Thyroid
 Feedback regulation

Hormones have a particular set point that is

controlled by:

 downregulating stimulatory pathways

when the set point is exceeded

 upregulating stimulatory pathways when

hormone levels fall below the set point
Feedback regulation

Mid-cycle
estradiol-
induced LH
secretion
 Feedback regulation: HPT axis

Hypothalamic-Pituitary-Thyroid axis
 Pulsatility of hormone secretion

 Several hormones are secreted in a pulsatile fashion (e.g., GnRH, TRH, GH, insulin,

etc.) and hormonal rhythms are used to adapt to environmental changes, such as daily

light-dark cycle, sleep, meals, stress and seasonality.

 Hormone rhythms have important implications for endocrine testing and treatment.

 Biomarkers to circumvent hormonal fluctuations: 24-hour urinary free cortisol (UFC),

Insulin-like Growth Factor 1 (IGF-1, a relatively stable biologic marker of GH action), etc.
Pulsatility of hormone secretion: examples

HPG axis Pancreas

Pancreas

Insulin
release

Jameson 2007; Hellman et al. 2007

Circadian hormone rhythms

Gamble et al. 2014, Nat Rev Endocrinol

 Hormone transport

 Most steroid hormones and many peptide hormones circulate in association with

binding proteins, which are globulin proteins synthesized primarily in the liver.

Hormone Hormone-binding protein(s)

Cortisol Cortisol-binding globulin (CBG) or transcortin
Sex hormones (androgens and estrogens) Sex hormone-binding globulin (SHBG)

Thyroid hormones (T3 and T4) • Thyroxine-binding globulin (TBG)

• Albumin
• Thyroxine-binding prealbumin (TBPA) or
transthyretin (TTR)
Growth hormone (GH) GH-binding protein (GHBP)
Insulin-like growth factors: IGF-1 and IGF-2 Multiple IGF-binding proteins (IGFBPs)
 Hormone action through receptors

 Hormones produce their biologic effects through interaction with high-affinity receptors

that are, in turn, linked to one or more effector systems within the cell.

 Hormone receptors can be divided broadly into two categories, namely:

a. Membrane receptors  these receptors primarily bind peptide hormones, neurotransmitters

and small molecules that are not able to cross the plasma membrane (e.g., catecholamines,

dopamine)

b. Nuclear receptors  these receptors bind small, lipid-soluble molecules that diffuse or are

transported across the cell membrane (e.g., thyroid hormone, steroids, vitamin D)
 Permissiveness

Permissiveness (permissive effect) is a

biochemical phenomenon in which the presence

of one hormone is required in order for another

hormone to exert its full effects on a target cell.

*A hormone increases another hormone’s effectiveness mainly by

up-regulating the receptor of the second hormone.

Example: thyroid hormones exert permissive effects on the actions of

catecholamines by up-regulating beta-adrenergic receptors.

a) Membrane receptors

Endocrinology: Adult and Pediatric (Seventh Edition)

 a) Membrane receptors

 Membrane receptors can be divided into several major groups on the basis of

structural similarities and signaling pathways:

1. Seven transmembrane domain G protein-coupled receptors (GPCRs)

2. Tyrosine kinase receptors (TKRs)

3. Cytokine receptor family

4. Transforming growth factor-beta (TGF-b) family serine kinase receptors

 a) Membrane receptors

 Membrane receptors can be divided into several major groups on the basis of

structural similarities and signalling pathways:

1. Seven transmembrane domain G protein-coupled receptors (GPCRs)

2. Tyrosine kinase receptors (TKRs)

3. Cytokine receptor family

4. Transforming growth factor-beta (TGF-b) family serine kinase receptors

 1. G protein-coupled receptors (GPCRs)
(Hormone)
GPCRs (also known as «seven-(pass)-transmembrane

domain receptors» or «serpentin receptors») bind a broad

array of hormones, including:

• Glycoprotein polypeptide hormones: e.g., FSH, LH, TSH

• Polypeptide hormones: e.g., PTH, glucagon

Inactive state

• Peptide hormones: e.g., TRH, GHRH, somatostatin

Active state

 GPCRs possess seven transmembrane-spanning (GHIH), calcitonin, vasopressin (ADH), oxytocin (OXT)
regions composed of hydrophobic a-helical domains, that
are connected by extracellular and intracellular loops.
• Catecholamines: epinephrine, dopamine
 G proteins form a heterotrimeric complex that is
composed of various Ga and Gb-g subunits.
 a) Membrane receptors

 Membrane receptors can be divided into several major groups on the basis of

structural similarities and signalling pathways:

1. Seven transmembrane domain G protein-coupled receptors (GPCRs)

2. Tyrosine kinase receptors (TKRs)

3. Cytokine receptor family

4. Transforming growth factor-beta (TGF-b) family serine kinase receptors

 2. Tyrosine kinase receptors (TKRs)

Tyrosine kinase receptors

(TKRs) transmit signal for
insulin and a variety of growth
factors, including:

• Insulin-like growth factor-1 (IGF-1)

• Platelet-derived growth factor (PDGF)

• Fibroblast growth factors (FGFs)

TKRs are transmembrane, immunoglobulin-like molecules containing an
extracellular ligand-binding region, a transmembrane region, and an
• Epidermal growth factor (EGF)
intracellular tyrosine kinase region that contains tyrosine residues whose
phosphorylation regulates signal transduction.
Insulin signal transduction pathway
is linked to TKRs
 a) Membrane receptors

 Membrane receptors can be divided into several major groups on the basis of

structural similarities and signalling pathways:

1. Seven transmembrane domain G protein-coupled receptors (GPCRs)

2. Tyrosine kinase receptors (TKRs)

3. Cytokine receptor family

4. Transforming growth factor-beta (TGF-b) family serine kinase receptors

 3. Cytokine receptor family
 Cytokine receptors are classified

according to their three-dimensional

(GHR, PRLR, EPOR,
TPOR, LEP-R)
structure.

 Growth hormone receptor (GHR),

prolactin receptor (PRLR),

erythropoietin receptor (EPOR),

thrombopoietin receptor (TPOR), leptin

receptor (LEP-R or OB-R) belong to the

Ligand (e.g., hormone) binding induces receptor interactions with
intracellular kinases (e.g., JAKs), which phosphorylate members of
the STAT family and other signaling pathways. The activated STAT class I cytokine receptor family, which
proteins translocate to the nucleus and promote expression of
target genes. includes more than 30 receptors.
Dehkhoda et al., 2018
 a) Membrane receptors

 Membrane receptors can be divided into several major groups on the basis of

structural similarities and signalling pathways:

1. Seven transmembrane domain G protein-coupled receptors (GPCRs)

2. Tyrosine kinase receptors (TKRs)

3. Cytokine receptor family

4. Transforming growth factor-beta (TGF-b) family serine kinase receptors

 4. Transforming growth factor-beta (TGF-b)
family serine kinase receptors

 These receptors bind a variety of

ligands, including TGF-b, and

hormones, such as inhibin,

activin, anti-müllerian hormone

(AMH), and bone morphogenetic

TGF-β receptors are a family of serine/threonine kinase receptors. These proteins (BMPs).
receptors bind to ligands through a heterodimeric receptor consisting of two
transmembrane subunits known as type I and type II receptors.

A group of downstream phosphorylation targets called the Smad proteins, upon

phosphorylation, migrate to the nucleus to activate and/or repress transcription
of target genes.
Greenspan's Basic and Clinical Endocrinology, Tenth Edition
 b) Nuclear receptors
 Nuclear receptors are ligand-activated transcription factors which alter transcription of target genes

by binding specific sequences of DNA known as “Hormone Response Elements” (HREs).

Nuclear receptors can be divided into two categories on the basis of their localization and mechanism of

action:

1. Type I nuclear receptors: in the absence of ligand, type I nuclear receptors are complexed with heat shock proteins

(HSP) in the cytoplasm. Hormone binding triggers dissociation of heat shock proteins (HSP), dimerization, and

translocation to the nucleus. These receptors bind to HREs as homodimers.

2. Type II nuclear receptors: unlike type I receptors, type II receptors are retained in the nucleus regardless of the

ligand binding status and in addition bind to HREs as heterodimers using retinoid X receptor (RXR) as obligate

partner. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins.
b) Nuclear receptors

Ligand binding
domain (LDB)
 Hormone response elements (HREs)

 Glucocorticoid response element (GRE)

 Mineralocorticoid response element (MRE)

 Estrogen response element (ERE)

 Thyroid hormone response element (TRE)
 Progesterone response element (PRE)
 Vitamin D response element (VDRE)
 Androgen response element (ARE)
 Retinoic acid response element (RARE)

 Retinoid X response element (RXRE)

 Type I nuclear receptors Type II nuclear receptors

HSP

Glucocorticoid Receptor (GR) Retinoic Acid Receptor (RAR)

Mineralocorticoid Receptor (MR) Retinoid X Receptor (RXR)
Estrogen Receptors (ERs) Vitamin D Receptor (VDR)
Progesterone Receptor (PR) Thyroid Hormone Receptor (TR)
Androgen Receptor (AR)
Avior et al., 2013
 Specificity-spillover phenomenon

 A given hormone has a primary affinity for its own receptor (e.g. vitamin D for

VDR), but it may also retain an affinity for the receptor of a hormone to which it is

related structurally.

 In some disease states, one or more manifestations of hormonal excess may be

caused by the interaction of one hormone with the receptor for a different

hormone.

 When one receptor is activated by a signal designed for another receptor, the event is

termed a “specificity spillover”.

Fradkin et al., NEJM 1989
 Specificity-spillover phenomenon

 At physiologic hormone concentrations, the affinity for the second receptor is often
low enough, relative to the concentration of reactants, that the consequences of the
spillover are negligible.

 Under pathologic conditions, when the hormone is present in excess, manifestations of

disease typically result from an excessive effect mediated through the hormone’s own
receptor. However, if the concentration of the hormone is sufficiently high, additional
serious biologic effects, characteristic of a second hormone, can be mediated
through an association of the first hormone with the receptor for the second hormone
(whether or not the second hormone is present).
Fradkin et al., NEJM 1989
 Specificity-spillover phenomenon
Apparent mineralocorticoid excess (AME) syndrome
Mineralocorticoid receptor (MR) shows a high affinity for both
aldosterone (the primary endogenous mineralocorticoid hormone)
and glucocorticoids (GCs: cortisol and corticosterone).

MR affinity for GCs is more than 10-fold higher than that of GR

itself. In addition, circulating GC concentration is 100- to 1,000-
fold higher with respect to that of aldosterone. Thus, GCs can bind
both to glucocorticoid receptor (GR) and MR.

In aldosterone-selective epithelial target tissues (e.g. kidney,

colon, salivary and sweat glands), the enzyme 11β-hydroxysteroid
dehydrogenase 2 (11β-HSD2) catalyzes the conversion of cortisol
to the inactive metabolite cortisone, thus preventing the illicit
2 activation of MR by GCs.
(11β-HSD2)
GCs can, however, also bind to MR, mimicking aldosterone
action if 11b-HSD2 activity is reduced (e.g. AME syndrome) or
when GC concentration exceeds the capacity of 11β-HSD2 to
inactivate cortisol to cortisone (e.g. Cushing’s syndrome),
resulting in higher sodium uptake, hypertension, increased
Raina et al., 2019 potassium excretion at the renal level and hypokalemia.
Implications for Clinical Endocrinology
 GPCR-related disorders

(Hormone)

 Gain-of-function mutation

 Loss-of-function mutation

Inactive state

Active state
 McCune-Albright syndrome

(Hormone)  Gain-of-function mutation

 Loss-of-function mutation

Syndrome arising from somatic activating mutations in GNAS gene, which

encodes the alpha-subunit of the Gs G protein-coupled receptor, resulting in

constitutive receptor activation.

Clinical features:

• Fibrous dysplasia
• « Café au lait » skin pigmentation
• Precocious puberty
• Pituitary and thyroid adenomas
• Bilateral adrenal hyperplasia
 Pseudohypoparathyroidism type 1A (PHP-1a)
 Gain-of-function mutation
(Hormone)

 Loss-of-function mutation
Disease caused by a loss-of-function mutation in GNAS gene, which encodes the

alpha-subunit of the Gs G protein-coupled receptor. It is inherited in an autosomal

dominant pattern and is associated with genetic imprinting (maternal origin).

Also known as
Clinical features: «Albright's hereditary osteodystrophy»
• Resistance to PTH, hypocalcemia
• Hypogonadism and hypothyroidism
• Round face, short stature, obesity
• Mental retardation to variable degree
• Subcutaneous calcifications and hypoplasia of dental enamel
• Short digits and metacarpals, especially metacarpals 4 and 5,
which produce dimple instead of knuckle
Rolla & Rodriguez-Gutierrez, NEJM 2012
 Steroid and thyroid hormone receptor
resistance syndromes
 Heritable defects caused by mutations in hormone receptor genes that prevent

hormone ligand binding to hormone receptor (mutations in ligand binding domain) or

alter hormone receptor-mediated transcriptional effects (mutations in DNA binding

domain).

 These disorders are characterized by a clinical phenotype suggesting hormone

deficiency, elevated levels of the circulating hormone ligand, and increased (or

inappropriately detectable) levels of the relevant trophic regulatory hormone

(e.g., ACTH, FSH, LH, or TSH).

 Clinical Endocrinology
Endocrine Diseases

 Hypofunction of an endocrine gland

 Hyperfunction of an endocrine gland

 Hormone receptor defects

 Defects in second messengers and intracellular signaling

 Hypofunction of an endocrine gland
Etiology

 Congenital defects in hormone synthesis

 Autoimmune destruction of the endocrine gland

 Surgical or traumatic injury to the endocrine gland

 Endocrine gland infiltration (tumors, infectious diseases, infiltrative and

granulomatous disorders)
 Hyperfunction of an endocrine gland
Etiology

 Hormone-secreting tumors

 Autoimmune diseases leading to hyperfunction of the endocrine gland

 Inflammatory or infectious diseases

 Iatrogenic or factitious causes

 Ectopic hormone production