664 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

39% of adults are overweight and 13% are obese. common cause of chronic kidney disease, is asso-
Globally, more than 340 million children were ciated with hypertension, and increases the risk
overweight or obese in 2016.14 Diabetes is a lead- of age-related cognitive losses. Obesity has sim-
ing cause of cardiovascular disease, the top cause ilar health-related consequences as diabetes, as
of death around the world. It is also the most well as increasing the risk of many cancers.

Principles of Endocrine Function

Christine Yedinak

The endocrine system functions to maintain homeo- (hypofunction) and hormone excess (hyperfunction).
stasis by modulating tissue and organ function through Dysfunction may also be primary or secondary. Primary
the actions of blood-borne and locally acting hor- dysfunction occurs when the deficiency or excess is
mones. Similar to the autonomic nervous system, the caused by abnormality of the main endocrine organ,
endocrine activity links detection of key body variables and secondary dysfunction occurs when a controlling
(including blood osmolality, volume, and pressure; hormone or other regulatory aspect is abnormally reg-
blood glucose; and circadian signaling, among others) ulated. Laboratory evaluation can distinguish between
with regulated secretion of hormones to maintain the these two possibilities, usually by measuring the endo-
stability of those variables. Differing from the nervous crine hormone and its controlling hormones or factors.
system, with its direct contact between effector cell Another mechanism of endocrine disease is altered
(neuron) and postsynaptic target tissue, endocrine tissue responsiveness to the hormone, in which case
glands secrete hormones into the bloodstream where evaluation depends less on measuring hormone levels
they travel through the circulation to act on target tis- and more on evaluating tissue responses. Management
sues throughout the body. Hormones have rapid and of endocrine disorders aims to correct the dysfunction
slow actions regulating metabolic activity, growth and (e.g., by removing a hormone-hypersecreting tumor,
development, reproductive functions, sleep, mood, as in Cushing disease, or by hormone replacement
and activity of the other organ systems. The endocrine after glandular failure, as in insulin treatment of type
glands and tissues discussed in this chapter include 1 diabetes).
the hypothalamus, pituitary, adrenal, thyroid, ovaries,
testes, and pancreas, and contributions of parathyroid
hormone (PTH) are highlighted in the topic of osteo- HORMONE STRUCTURES
porosis, within the section on female reproductive
Copyright © 2020. Springer Publishing Company, Incorporated. All rights reserved.

function. Hormones are classified by derivation, structure, func-

The amount (magnitude) and rate of hormone tion, or solubility. Broad classifications include amines
synthesis and secretion to maintain homeostasis is (modified from amino acids), peptides (short amino
controlled by feedback mechanisms (negative and pos- acid chains), proteins (longer amino acid chains), and
itive) and endogenous rhythms. Negative feedback sup- steroids (synthesized from cholesterol; Table 17.1).
presses hormone production once an excess state is Hormone synthesis and secretion differ by system,
achieved, whereas positive feedback stimulates further and details of synthesis are described in the context of
hormone production and release. Endogenous rhythms the individual systems discussed in the main sections
are recurrent patterns of hormone secretion. These are of this chapter. In general, endocrine cells either will
largely circadian, recurring every 24 hours. Circadian have a high level of gene expression for a peptide or
rhythms are often based on light/dark cycles and are protein hormone (such as arginine vasopressin [AVP] or
controlled by the “clock mechanism” of the hypothala- insulin) or will have a unique set of enzymes to synthe-
mus. Ultradian rhythms have cycles that occur several size an amine, thyroid, or steroid hormone. Protein and
times over the course of the day. Infradian rhythms peptide hormones are usually synthesized as pre-pro
are longer than a day (such as the menstrual cycle) and proteins, with a signal sequence that is used to direct
may be affected by seasonal, environmental, or exoge- them to secretory vesicles for secretion. After the sig-
nous changes such as food intake. These rhythms allow nal sequence is removed by enzymes, the resulting pro
physiological adaptation to environmental changes and protein requires further folding, cleaving, and processing
mediate changes of state associated with longer-term to be ready for secretion. The hormone insulin, for exam-
biological processes such as growth and reproduction. ple, is the cleavage product of proinsulin that has been
Disorders of the endocrine system tend to fall into folded and cleaved, resulting in a two-chain structure.
two categories: absolute or relative hormone deficiency Steroid hormone synthesis, on the other hand, requires
Advanced Physiology and Pathophysiology : Essentials for Clinical Practice, edited by Nancy Tkacs, et al., Springer Publishing Company, Incorporated, 2020. ProQuest Ebook Central,
http://ebookcentral.proquest.com/lib/apus/detail.action?docID=6143160.
Created from apus on 2024-01-29 16:32:10.
 Chapter 17 • Endocrine System 665

TABLE 17.1 Examples of Hormone Structures

Hormone Class Components Example(s)

Amine hormone Amino acids with modified Norepinephrine

groups (e.g., norepinephrine
OH
is synthesized by enzymatic
modifcation of the amino acid NH2
tyrosine

HO

OH

Peptide hormone Short amino acid chains Oxytocin

Gly

Leu

Pro

Cys Asn

Cys Gln

Tyr Ile

Protein hormone Long amino acid chains Growth hormone

Copyright © 2020. Springer Publishing Company, Incorporated. All rights reserved.

Steroid hormone Derived from the lipid Testosterone Progesterone

cholesterol
CH3

OH C O
H3C H3C

H3C H3C

O O

Advanced Physiology and Pathophysiology : Essentials for Clinical Practice, edited by Nancy Tkacs, et al., Springer Publishing Company, Incorporated, 2020. ProQuest Ebook Central,
http://ebookcentral.proquest.com/lib/apus/detail.action?docID=6143160.
Created from apus on 2024-01-29 16:32:10.
 666 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

cell synthesis or uptake of cholesterol and the presence neuroendocrine signaling. This type of signaling char-
of enzymes that modify cholesterol into the final steroid acterizes neurons located in the hypothalamus that
hormone. Secretion of most hormones is by regulated synthesize and secrete their hormone from their axon
exocytosis. Thyroid hormone synthesis differs from all terminals into the bloodstream. This hybrid of neuronal
other hormones in occurring extracellularly within the features (axon terminals as the site of release, action
colloid of thyroid follicles, and thyroid hormone secre- potentials required for release) and endocrine features
tion occurs by colloid endocytosis, lysosomal degrada- (substance enters the bloodstream to travel to target
tion, and free hormone release. tissues) applies to hypothalamic releasing and inhibit-
ing hormones, as well as to the posterior pituitary hor-
mones vasopressin and oxytocin.
CELL SIGNALING BY HORMONES When hormones bind to their specific receptors on
target cell membranes or diffuse into the cell, they acti-
Hormones do not only act on distant targets. Other vate a cascade of intracellular activities or nuclear gene
modes of signaling include autocrine (in which the transcription that modulates cell function (Figure 17.2).
hormone-producing cell also has receptors for the Endocrine signaling pathways incorporate the steps of
hormone it synthesizes and secretes) and paracrine reception, transduction, and cellular response, falling
(in which the hormone acts on adjacent and nearby into two broad classes of intracellular mechanisms:
cells; Figure 17.1). Additionally, some of the hor-
mones described in this chapter fall into a category of 1. Water-soluble (hydrophilic) hormones travel in
blood plasma and bind to cell surface receptors to
generate rapid cellular changes via second mes-
sengers (Figure 17.2a). These include amines,
Endocrine Target cell
peptides, and protein hormones, for example, epi-
nephrine, vasopressin, and adrenocorticotropic hor-
mone (ACTH). Many membrane hormone receptors
are of the G protein–coupled type, which alter ade-
nylyl cyclase or phospholipase C activity with recep-
Endocrine cell Bloodstream tor binding. Other hormone receptors incorporate a
Autocrine Paracrine tyrosine kinase domain, or associate with accessory
proteins that are tyrosine kinases, to achieve cellular
Receptor
responses as described in Chapter 4, Cell Physiology
and Pathophysiology (Figure 17.2b).
2. Steroid and thyroid hormones are lipid soluble
(hydrophobic) and travel in blood plasma on pro-
tein carriers that prolong their duration in the cir-
Neuroendocrine culation and length of action. The major mechanism
Copyright © 2020. Springer Publishing Company, Incorporated. All rights reserved.

Target cell
of action of these hormones is to cross the plasma
membrane, binding to receptors in the cytoplasm
or in the nucleus, ultimately binding to DNA to alter
gene expression (Figure 17.2c).

Bloodstream These generalized mechanisms are not the only possi-

ble modes of signaling. In fact, water-soluble hormones
FIGURE 17.1 Modes of hormone signaling. Classic conce­ can act through their second messengers to alter gene
ption of endocrine signaling is the release of a hormone transcription and translation. Steroid and thyroid hor-
from specialized endocrine gland cells into the bloodstream, mones can also have short-term actions in the cyto-
where it travels to distant tissues to have its biological plasm, in addition to their roles in altering protein
effect. Many endocrine gland cells have autoreceptors transcription and translation.15
for the hormones they secrete, and are thus modulated Table 17.2 provides a comprehensive list of endo-
by autocrine signaling. Paracrine signaling refers to the
crine glands and hormones—their structure, size,
modulation of an adjacent or nearby cell by hormone
targets, and major functions. Other hormones are
diffusing from its secretion site. Finally, neuroendocrine
signaling characterizes the actions of neurons located synthesized outside the brain and classical endo-
within the nervous system, with axons that project to crine organs, and are described in the context of their
the pituitary stalk or posterior pituitary gland. The axons main tissue sources and actions; for example, gas-
terminate on blood vessels, releasing hormones that travel trointestinal hormones are described in Chapter 13,
to target tissues to exert their biological effects. Gastrointestinal Tract.

Advanced Physiology and Pathophysiology : Essentials for Clinical Practice, edited by Nancy Tkacs, et al., Springer Publishing Company, Incorporated, 2020. ProQuest Ebook Central,
http://ebookcentral.proquest.com/lib/apus/detail.action?docID=6143160.
Created from apus on 2024-01-29 16:32:10.
 Chapter 17 • Endocrine System 667

PLC AC

q s
Phospholipase Adenylyl
Receptor C–linked Receptor cyclase–linked

(a) G protein–coupled receptor

Nucleus
Complex
NR
ligand-NR

Ligand

HREs
DNA

Transcription

mRNA

mRNA
Translation
P P
P
P P
Peptides
Cytoplasm
(b) Tyrosine kinase–linked (c) Nuclear receptor mechanism
receptor

FIGURE 17.2 Three common mechanisms of hormone action are shown here. (a) and (b) Water-
soluble hormones bind to cell surface receptors that are either G protein–coupled or linked to
activation of tyrosine kinase activity to exert intracellular effects. (c) Steroid and thyroid hormones
cross the plasma membrane and bind to a cytosolic or nuclear receptor, ultimately binding to DNA.
The result of receptor activation is to exert long-term changes by changing target cell transcription
and translation.
Copyright © 2020. Springer Publishing Company, Incorporated. All rights reserved.

AC, adenylyl cyclase; HRE, hormone-response element; mRNA, messenger RNA; NR, nuclear
receptor; P, phosphate; PLC, phospholipase C.

TABLE 17.2 Hormones and Their Functions

Endocrine Source
or Gland Hormone/Class Main Function of Hormone

Hypothalamus Thyrotropin releasing hormone (TRH) Stimulates anterior pituitary thyrotropes to release TSH
Peptide: 3 aa

Somatostatin (SST) Inhibits release of several anterior pituitary hormones,

Peptide: 14 or 28 aa including GH

Gonadotropin releasing hormone (GnRH) Stimulates anterior pituitary gonadotropes to release FSH
Peptide: 10 aa and LH

Corticotropin releasing hormone (CRH) Stimulates anterior pituitary corticotropes to release ACTH
Peptide: 41 aa

Growth hormone releasing hormone (GHRH) Stimulates anterior pituitary somatotropes to release GH
Peptide: 44 aa

(continued )
Advanced Physiology and Pathophysiology : Essentials for Clinical Practice, edited by Nancy Tkacs, et al., Springer Publishing Company, Incorporated, 2020. ProQuest Ebook Central,
http://ebookcentral.proquest.com/lib/apus/detail.action?docID=6143160.
Created from apus on 2024-01-29 16:32:10.
 668 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

TABLE 17.2 Hormones and Their Functions (continued )

Endocrine Source
or Gland Hormone/Class Main Function of Hormone

Anterior pituitary Thyroid stimulating hormone (TSH) Stimulates thyroid gland growth, promotes T4 and T3
Glycoprotein: common α subunit— synthesis and secretion
89 aa; unique β subunit—112 aa

Luteinizing hormone (LH) Females: stimulates ovarian sex steroid production,

Glycoprotein: common α subunit— LH mid-cycle peak initiates ovulation
89 aa; unique β subunit—115 aa Males: stimulates testis synthesis and secretion of testosterone

Follicle-stimulating hormone (FSH) Females: stimulates ovarian early follicular cycle follicle
Glycoprotein: common α subunit— development and preparation for ovulation
89 aa; unique β subunit—115 aa Males: stimulates testis synthesis and secretion of testosterone

Growth hormone (GH) Promotes growth of bones and organs; promotes muscle
Protein: 190 aa protein synthesis, regulates metabolism of fat and liver

Prolactin (PRL) Stimulates breast development and milk production

Protein: 198 aa

Adrenocorticotropic hormone (ACTH) Stimulates adrenal gland growth and hormone secretion,
Protein: 39 aa particularly cortisol secretion

Posterior pituitary Vasopressin (AVP, antidiuretic hormone) Controls renal water retention to regulate blood volume and
Peptide: 9 aa pressure, also functions as vasoconstrictor

Oxytocin (OT) Stimulates uterine contraction, initiates milk ejection

Peptide: 9 aa (let-down)

Thyroid gland Thyroxine (T4) Maintains normal functions of most tissues, increases the
Thyroid hormone body’s metabolic rate

Triiodothyronine (T3) More active than T4, maintains normal functions of most
Thyroid hormone tissues, increases the body’s metabolic rate, required for
normal development and function of the brain

Parathyroid glands Parathyroid hormone (PTH) Increases blood calcium level by promoting absorption (from
Protein: 84 aa intestine or kidneys) or release (from bone breakdown)
Copyright © 2020. Springer Publishing Company, Incorporated. All rights reserved.

Adrenal cortex Cortisol Targets most tissues, particularly liver, adipose, muscle, immune
Steroid cells; many physiological functions, including metabolic
regulation, blood pressure maintenance, immune modulation

Aldosterone Acts on the kidney to promote sodium retention and

Steroid potassium excretion—required for normal blood
pressure maintenance

Androgens (dehydroepiandrosterone, Act on many target tissues to promote the development

DHEA, DHEA-sulfate) and maintenance of male characteristics
Steroid

Adrenal medulla Epinephrine and norepinephrine Act on many target tissues to increase blood pressure, blood
Catecholamines glucose, catabolism—active in stress responses

Pancreas Insulin Targets liver, muscle, and fat, lowers blood glucose levels,
Protein: 51 aa promotes growth, anabolic hormone

Glucagon Targets liver, raises blood glucose levels, catabolic hormone

Peptide: 29 aa

Somatostatin (SST) Acts locally within pancreas, paracrine action inhibits

Peptide: 14 or 28 aa glucagon and insulin release

(continued )

Advanced Physiology and Pathophysiology : Essentials for Clinical Practice, edited by Nancy Tkacs, et al., Springer Publishing Company, Incorporated, 2020. ProQuest Ebook Central,
http://ebookcentral.proquest.com/lib/apus/detail.action?docID=6143160.
Created from apus on 2024-01-29 16:32:10.
 Chapter 17 • Endocrine System 669

TABLE 17.2 Hormones and Their Functions (continued )

Endocrine Source
or Gland Hormone/Class Main Function of Hormone

Ovary Estrogens Target breasts, uterus, ovary, and other female reproductive
Steroid structures to develop and maintain female primary
and secondary sexual characteristics; regulate uterine
proliferation during menstrual cycle

Progesterone Promotes the development of female sexual characteristics,

Steroid required for pregnancy maintenance

Testis Testosterone Promotes the development and maintenance of male sexual

Steroid characteristics and reproductive competence

aa, amino acids.

Source: From EndocrineSurgeon.Co.uk. What are the functions of the different types of hormones? http://www.endocrinesurgeon.co.uk/index.
php/what-are-the-functions-of-the-different-types-of-hormone.

CIRCULATING HORMONE LEVELS TABLE 17.3 Hormones and Their Binding Proteins

Hormones can circulate in plasma either freely dis- Hormone Binding Proteins
solved in plasma (amines, peptides, and some proteins) Cortisol Corticosteroid-binding globulin
or bound to other molecules such as serum binding Albumin
proteins (steroid and thyroid hormones). The major-
ity of circulating steroid and thyroid hormone mole- Adrenal androgens Albumin
cules are bound to plasma protein carriers, but a small Estrogen Albumin
fraction, generally <10%, are unbound or “free.” The Sex hormone–binding globulin
hormone molecules spontaneously alternate between
bound and free states, in an equilibrium relationship Progesterone Albumin
that depends on the relative concentrations of binding Testosterone Sex hormone–binding globulin
protein, bound hormone, and free hormone. The free
fraction is able to enter cells, bind to its receptors, and Thyroid hormones Thyroxine-binding globulin
exert intracellular effects, and is therefore biologically (T3 and T4) Transthyretin
active. The concentration of bound hormone in plasma Albumin
provides a readily accessible pool to maintain hormone
Copyright © 2020. Springer Publishing Company, Incorporated. All rights reserved.

Insulin-like growth Six different IGF binding proteins

activity, stabilizing the levels of free hormone and pro- factor (IGF)
tecting the hormone molecules from rapid degradation
or renal excretion. Laboratory tests for protein-bound Growth hormone Growth hormone–binding protein
hormones may measure either the total hormone Source: From EndocrineSurgeon.co.uk. What are the functions of
(bound plus free) or just the free fraction, as noted later the different types of hormone? http://www.endocrinesurgeon.co.uk/
in the chapter where pertinent. Examples of hormones index.php/what-are-the-functions-of-the-different-types-of-hormone.
and their binding proteins are listed in Table 17.3.
Secretion of pituitary hormones is characterized by
pulsatility (bursts of secretion occurring throughout Hormones have widely varying half-lives in the
the day and night, separated by pauses) and rhythms. circulation. This is an important factor to consider
Knowledge of these patterns is the key to interpreting bio- when measuring hormone levels or clinically manag-
chemical testing of hormonal levels. As described later, ing replacement hormone doses and dosing intervals.
most pituitary hormones, including adrenocorticotropic When providing exogenous hormone replacement,
hormone (ACTH), growth hormone (GH), and prolactin the time interval to when a drug dose reaches steady
(PRL), are secreted in pulses of varying time intervals. state is intimately connected to the rate of decay of
Pulsatility is measured by the frequency and amplitude the hormonal signal, which is dependent on factors
of episodic hormone production, and encompasses the such as rate of synthesis and secretion, degradation,
ultradian, circadian, and infradian rhythms mentioned and transport. For example, thyroxine (T4) has a cir-
previously. For this reason, some hormones are better culating half-life of 7 days and takes over 1 month to
measured after a stimulation (also known as provocation) reach steady state. In contrast, triiodothyronine (T3)
test; for example, if their normal peak is during sleep. has a half-life of 1 day. The half-life of steroids such as

Advanced Physiology and Pathophysiology : Essentials for Clinical Practice, edited by Nancy Tkacs, et al., Springer Publishing Company, Incorporated, 2020. ProQuest Ebook Central,
http://ebookcentral.proquest.com/lib/apus/detail.action?docID=6143160.
Created from apus on 2024-01-29 16:32:10.
 670 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

− Central nervous system −

− or +

Hypothalamus

Long-loop Short-loop
negative − Releasing hormones Inhibiting factors negative
feedback feedback
+ −

Anterior pituitary

Trophic hormone
+

Target organs/tissues
+ Stimulus

− Inhibits
Hormones/tissue response

FIGURE 17.3 Secretion of anterior pituitary hormones is under the control of releasing and
inhibiting hormones secreted by hypothalamic neuroendocrine cells onto blood vessels of the
pituitary stalk. Pituitary trophic hormones (ACTH, TSH, LH, and FSH) stimulate target gland
hormone secretion (adrenal glucocorticoids, thyroid hormone, and gonadal steroids, respectively).
Target gland hormones provide feedback (usually negative) to inhibit pituitary and hypothalamic
hormone secretion.
ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone;
TSH, thyroid-stimulating hormone.

glucocorticoid analogues varies widely. This has impli-

cations for the timing of beneficial drug effects, as well
as negative consequences such as suppression of the
hypothalamic-­pituitary-adrenal (HPA) axis by exoge-
Copyright © 2020. Springer Publishing Company, Incorporated. All rights reserved.

nous steroids. 3

2
4

HORMONE CONTROL AXES

Set point
Both negative and positive feedback regulation govern (optimal
endocrine hormone secretion to maintain physiological 1 conditions)
homeostasis. Negative feedback regulation is more com- Corrective action
mon. For example, increased blood glucose levels stimu-
late secretion of the hormone insulin, which subsequently
promotes cell glucose uptake, lowering blood glucose
back to normal levels. Secretion of certain target gland
hormones (thyroid hormone, cortisol, testosterone, estro-
gen, and progesterone) is controlled by hypothalamic
FIGURE 17.4 In a negative feedback system, deviation of a
and pituitary hormones, which in turn are regulated by signal (blood glucose, blood pressure, stress hormone level)
feedback exerted by those target gland hormones. Once from a set point (for example, levels rising between times
target gland hormone level exceeds a threshold, this 1–2) is detected by sensors, resulting in a corrective change
exerts negative feedback on both the pituitary cells pro- of hormone output at time 3. At time 4, the signal returns to
ducing the trophic hormone and the hypothalamus to set point. Decreases from the set point are also compensated
suppress the releasing hormone (Figures 17.3 and 17.4). by corrective actions that return the signal to the set point.

Advanced Physiology and Pathophysiology : Essentials for Clinical Practice, edited by Nancy Tkacs, et al., Springer Publishing Company, Incorporated, 2020. ProQuest Ebook Central,
http://ebookcentral.proquest.com/lib/apus/detail.action?docID=6143160.
Created from apus on 2024-01-29 16:32:10.