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Vertebrate Endocrinology

Fifth Edition

David O. Norris, Ph.D.

Professor Emeritus,
Department of Integrative Physiology,
University of Colorado at Boulder,
Colorado, USA

James A. Carr, Ph.D.

Professor,
Faculty Director, Joint Admission Medical Program,
Department of Biological Sciences,
Texas Tech University,
Lubbock, Texas, USA

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD • PARIS

SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO

Academic Press is an Imprint of Elsevier

4 Vertebrate Endocrinology

(A)

(B)
Cells accumulate toxins, nutrients, etc.

Toxins
Nutrients
Receptors

Bioregulators

FIGURE 1-2 Origins of chemical communication. (A) Early cells living in the primordial seas developed “receptors” (here shown only on the cell
membrane) for recognition of water-soluble toxins (blue circles) and nutrients (red squares) as well as internal “receptors” (not shown) for lipids that could
readily pass through the membrane. Some of these “receptors” transferred these molecules into the cell for metabolism or detoxification. (B) In addition to
accumulating molecules intracellularly, early cells also released special molecules into the environment that were detected via receptors on other cells and
served as a mechanism for cell-to-cell communication. Various features of these ancient mechanisms for accumulation, detoxification, metabolism, and
chemical communication have persisted in one form or another in all living cells to this day.

inhibitors, and immune regulators. If cytocrines also affect
the emitting cell, they are sometimes termed autocrines.
When they affect other cell types, they are called para-
crines. However, both types of local cytocrine secretion
into the general extracellular fluids are sometimes loosely
referred to as paracrine secretion.
Chemicals released from neurons into the cerebrospinal
fluid (CSF) do not quite fit the definition of neurohormone,
as they are released into a filtrate of blood, but they do
not quite fit the definition of paracrine secretion, either.
For our purposes, we will refer to these bioregulators as
neurohormones.
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates 5

Ordinary FIGURE 1-3 Bioregulator organization.

neurons Chemical communication involves neurocrines,
including neurotransmitters or neuromodulators
(1) and neurohormones (2), as well as hormones
(3) and autocrine/paracrine regulators (4). The liver
1 and kidney serve as major sites for the metabolism
1 and excretion of bioregulators.

Neurosecretory
(ns) neuron
Autocrine
Neurosecretory 2
(ns) neuron

4
1

Endocrine Paracrine
2 cell

Liver Kidney Target

cell cell cell

Metabolism Excretion Effect

Intracellular chemical messengers that govern intra-
cellular events have been called intracrines. These intra-
crine bioregulators would include chemicals such as the
second messengers and transcription factors that are dis-
cussed in Chapter 3.
In its broadest sense, the study of bioregulation may
include specific chemical messengers released by one
organism into its environment that may affect the physi-
ology or behavior of other individuals of that species or
even of another species. A good name for these substances
might have been “exocrines,” but that term had already
been assigned to the products of exocrine glands
(e.g., salivary glands, sweat glands, mammary glands, and
portions of the liver and pancreas) that secrete their prod-
ucts into ducts through which the secretions are conveyed
to their sites of action on the free surface of the epithelium
in such places as the digestive tract or the skin. These
externally secreted bioregulators are called “ecto-
hormones” or semiochemicals (semio, signal). Three
subclasses of semiochemicals have been identified on
functional bases. Pheromones are semiochemicals that act
only on other members of the same species. Primer
pheromones usually initiate a series of physiological
events such as gonadal maturation. Signal or releaser
pheromones trigger immediate behavioral responses such
as sexual attraction or copulation. Allelomones are inter-
specific semiochemicals and are further separated into two
types. If only the emitter of the semiochemical benefits
from the effect on the other species, the allelomone is called
an allomone. The well-known odor released by skunks is
a dramatic example of an allomone that protects the skunk
from would-be predators. When only the recipient species
benefits, the allelomone may be termed a kairomone. The
release of the simple metabolite l-lactate in the sweat of
humans attracts female mosquitoes, which obtain the blood
meal necessary for their reproduction. l-Lactate, then,
could be classified as a kairomone, for there is no obvious
benefit to the emitter and in fact it may harm the emitter.
6 Vertebrate Endocrinology
In summary, intraorganismal bioregulation can be
classified as endocrine (hormones), neurocrine (neuro-
transmitters, neuromodulators, neurohormones), paracrine
(cytocrines, autocrines), or intracrine (intracellular regu-
latory messengers). Semiochemicals (pheromones and
allelomones) are specialized for interorganismal commu-
nication. A listing of these types of bioregulators and their
definitions are provided in Table 1-2.
Most bioregulators are peptides, proteins, or derivatives
of amino acids. Some are lipids (e.g., steroids) and still
others are nucleotides or nucleotide derivatives. A discus-
sion of the chemical nature of regulators, how they are
synthesized, how they produce their effects on targets, and
how they are metabolized is the subject of Chapter 3.
However, before examining these bioregulators more
closely, we must consider some more general features of
bioregulatory systems.
TABLE 1-1 Some Mammalian Neurocrine Bioregulators*
Class of Regulator Example
Nonpeptides Acetylcholine (ACh)
Carbon monoxide (CO)
Dopamine (DA)
Epinephrine (E)
g-Aminobutyric acid (GABA)
Glutamate
Nitric oxide (NO)
Norepinephrine (NE)
Serotonin (5-HT)
Hypothalamic-releasing Corticotropin-releasing hormone
neuropeptides (CRH)
Gonadotropin-releasing hormone
(GnRH)
Prolactin-releasing hormone (PRH)
Somatostatin (SS or GHRIH)
Thyrotropin-releasing hormone (TRH)
Other neuropeptides Angiotensin II (Ang-II)
Arginine vasopressin (AVP)
Atrial natriuretic peptide (ANP)
Brain natiuretic peptide (BNP)
Cholecystokinin (CCKg)
Ghrelin
Insulin
Kisspeptin (Kp)
Leptin
Neuropeptide Y (NPY)
Neuropeptide YY (PYY)
peptide histidine isoleucine (PHI)
Substance P (SP)
Vasoactive intestinal peptide (VIP)
*Some of these molecules may function only as a neurotransmitter, neu-
romodulator, neurohormone, or paracrine regulator whereas others may
perform multiple roles.
A bioregulator has a distinct life history analogous
to that of an organism, as illustrated in Figure 1-5 for
a typical hormone. A bioregulator is born (synthesis), may
exist first as an immature stage (inactive precursor mole-
cule) that later is transformed to a mature form (metabo-
lized to an active molecule), has a life (binds to receptors
and produces an effect), and dies (is metabolized and/or
excreted). It only lacks the ability to reproduce itself.
IV. GENERAL ORGANIZATION OF
BIOREGULATORY SYSTEMS
As stated above, the endocrine system and the nervous
system are the sources for most of the chemical messengers
we have defined as bioregulators. Traditionally, the verte-
brate neuroendocrine system includes the brain and the
pituitary gland plus the classical endocrine glands they
control: the thyroid gland, the paired adrenal glands and
gonads (testes and ovaries), and the liver. In addition, there
are independent endocrine bioregulatorsdthat is, those
not directly under the influence of the brain and/or pitui-
tary. This would include the adipose tissue, parathyroid
glands, thymus, heart, endocrine pancreas, organs of
the gastrointestinal tract, pineal gland, and kidney. The
major focus of this textbook is on the neuroendocrine
systems of mammals and non-mammalian vertebrates. The
independent endocrine glands are discussed for some
special cases (for example, regulation of calcium homeo-
stasis, which is discussed in Chapter 14) and when they
interact with the bioregulators of the neuroendocrine
system such as in the bioregulation of metabolism
(Chapters 12 and 13).
The vertebrate neuroendocrine bioregulatory system
(Figure 1-4) involves a major portion of the brain called the
hypothalamus, that portion of the brain located directly
above and anterior to the pituitary gland. The detailed
organization and operation of this system are described in
Chapters 4 and 5. Special groups of neurosecretory neurons
in the hypothalamus produce a variety of neurohormones.
Some of these neurohormones (i.e., releasing and release-
inhibiting hormones) control the secretion by the pituitary
gland of peptide and protein hormones called tropic
hormones (tropic is derived from the Greek word trophe,
referring to nutrition). These tropic hormones regulate the
endocrine activities of the thyroid gland (secretes thyroid
hormones; see Chapters 6 and 7), the adrenal cortex
(secretes corticosteroids; Chapters 8 and 9), the gonads
(secrete reproductive steroids; Chapters 10 and 11) and the
liver (secretes an essential factor for growth; Chapter 4).
Furthermore, some tropic hormones influence more general
aspects of growth, metabolism, and reproduction and affect
many non-endocrine target tissues. Additional neurohor-
mones (vasopressin and oxytocin) are stored in part of the
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates 7

Endocrine System Subdivisions

Neuroendocrine Endocrine (only)

Hypothalamus

Nonapeptides Releasing hormone(s)

Nonapeptide Pituitary
Hormone(s)
Tropic hormone(s)

Endocrine gland(s) Endocrine gland(s)

Hormone(s) Hormone(s)

Target organ(s) Target organ(s) Target organ(s)

Effect Effect Effect

FIGURE 1-4 Functional conceptualization of the endocrine system. Input from other endogenous or exogenous factors can affect every level of
regulation. The endocrine (only) glands typically respond to levels of chemicals in the blood, and, although innervated, their secretion is not directly
controlled by the nervous system. Nonapeptide targets include the kidney and mammary gland as well as reproductive and vascular smooth muscle.
Endocrine glands controlled by tropic hormones from the pituitary include the gonads, thyroid, adrenal cortex, and liver. Endocrine-only glands include
the parathyroids, kidneys, heart, adipose tissue, and others.

pituitary until they are needed (Chapters 4 and 5). Vaso- Table 1-3 is a partial listing of bioregulators that are
pressin influences kidney function, blood pressure, and discussed in this book. In addition to their names and
reproductive behavior, and oxytocin plays many repro- abbreviations, their sources, targets, and general effects on
ductive roles related to both physiology and behavior. the targets are provided.

TABLE 1-2 Types of Bioregulators

Agent Description Examples

Neurotransmitter Secreted by neurons into synaptic space Acetylcholine, dopamine, substance P, GABA

Neuromodulator Secreted by neurons into synaptic space; modulates Endorphins and various other neuropeptides
sensitivity of postsynaptic cell to other neurotransmitters
Neurohormone Secreted by neurons into the blood or CSF; may be stored TRH, CRH, oxytocin, dopamine
in neurohemal organ prior to release
Hormone Secreted by specialized nonneural cells into the blood Thyroxine, GH, insulin
Cytocrine Secreted by cells into the surrounding extracellular fluid; Somatostatin, norepinephrine
these local regulators typically travel short distances to
nearby target cells
Paracrine Secreted by cells and affect other cell types Embryonic inducers, somatostatin, interleukins
Autocrine Secreted by cells and affect emitting cell/type Mitogenic agents, interleukins
Intracrine Intracellular messengers; typically mediators of other cAMP, DAG, IP3, cGMP, calmodulin, calcium ions
regulators that bind to membrane receptors
Semiochemical Secreted into environment Pheromones, allelomones

See Appendix A for explanation of abbreviations.

8 Vertebrate Endocrinology
FIGURE 1-5 Life history of a hormone.
A hormone is “born” in an endocrine cell
and spends its short life “free” in the blood
or bound to binding proteins. It may be Neural or blood-
borne stimulus
metabolized and/or excreted (“die”) before
or after it binds to a target cell where it
causes changes that result in its character-
istic effect. In some cases, the hormone is
– +
secreted in an inactive form and must be
metabolized to an active form before it can
bind to its receptor and produce an effect.
Endocrine cell
Hormone
Hormone metabolized
for secretion
Hormone metabolized
to more active form
Hormone binding protein
Receptors
V. CELL AND TISSUE ORGANIZATION
OF BIOREGULATORY SYSTEMS
Endocrine and neuroendocrine cells can be identified
easily on the basis of their cytological features as
specialized secretory cells (Figure 1-6). Peptide-secreting
cells have well-developed rough endoplasmic reticula
and typically contain many protein-filled storage granules
or vesicles (see Appendix F for a brief description of
cellular structures). Mitochondria of peptide-secreting
cells have flat, platelike cristae. The morphology and
content of the protein storage granules may be used to
differentiate specific types of endocrine cells. For
example, the various tropic hormone-secreting cells of
the anterior pituitary can be partially identified by the
differential sizes of their storage granules or by special
immunochemical methods (see Chapters 2 and 4). In
contrast, steroid-secreting cells have well-developed
smooth endoplasmic reticula, and their mitochondria
have tubular cristae (compare steroid- and peptide-
secreting cells as shown in Figure 1-6). Steroids are
usually not stored in their cells of origin but lipid droplets
containing cholesterol, the precursor steroid for their
synthesis, are commonly observed.
Not only are neurosecretory neurons and regular
neurons specialized elongated cells that are readily identi-
fiable but they also contain discrete synaptic vesicles
containing neurocrine products in their axonal tips that
characterize them as secretory cells. Neurosecretory
Excretion
Liver
Metabolism
Feedback
Target cell
Excretion
Kidney
neurons tend to be larger than ordinary neurons. Neurons
secreting peptides contain larger, dense granules than
those secreting non-peptides such as catecholamines or
acetylcholine. For example, the synaptic vesicles for
acetylcholine are 30 to 45 nm in diameter and those for
norepinephrine are about 70 nm, but peptide-containing
vesicles are 100 to 300 nm.
In the central nervous system, the cell bodies of
neurons are localized in groupings called nuclei, and their
axons often form specific tracts connecting to other nuclei,
blood vessels, or the cerebrospinal fluid, or they may exit
from the central nervous system as nerves. In fact,
neurosecretory neurons were first characterized as unique
because their cell bodies in neurosecretory nuclei and
axons in neurosecretory tracts contain materials that
stain with unique dyes, distinguishing these cells from
ordinary neurons. However, these general methods usually
did not distinguish between different kinds of neurose-
cretory neurons. Modern immunological techniques now
allow us to identify each type of neurosecretory or ordi-
nary neuron with respect to its particular secretions (see
Chapter 2).
Another factor that helped in the early identification
of endocrine cells was their anatomical relationship to
one another in forming discrete tissues (see Figure 1-7).
Many endocrine cells are specialized epithelial cells that
tend to be clumped in groups that are organized in one of
the following ways (see Appendix F for descriptions of
epithelia and other tissue types). The most common
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates 9

TABLE 1-3 The Mammalian Endocrine System: Major Secretionsa and Actions

Sourceb and Secretions Target Action

Anterior pituitary: produces tropic hormones

Glycoprotein tropic hormones
Thyrotropin (thyroid-stimulating hormone; TSH) Thyroid gland Synthesis and release of thyroid hormones

Luteinizing hormone (lutropin, LH) Gonads Androgen synthesis; progesterone

synthesis; gamete release

Follicle-stimulating hormone (follitropin, FSH) Gonads Gamete formation; estrogen synthesis

Nonglycoprotein tropic hormones
Growth hormone (somatotropin, GH) Liver, cartilage, bone, Synthesis of IGF, proteins
adipose, muscle
Prolactin (mammotropin, PRL) Mammary glands, epididymus Synthesis of proteins
Corticotropin (adrenocorticostimulating Adrenal cortex Synthesis of corticosteroids
hormone, ACTH)
Melanotropin (melanocyte- or melanophore- Melanin-producing cells Synthesis of melanin
stimulating hormone, MSH)
Others products
Tuberalin Prolactin cells Release of prolactin
Pituitary adenylate cyclase activating peptide Numerous pituitary cells Activates cAMP and enhances response
(PACAP) to releasing hormones
Hypothalamus: neurosecretory nuclei produce neurohormones
Hypothalamic-releasing hormones
Thyrotropin-releasing hormone (TRH) Anterior pituitary Releases TSH
Gonadotropin-releasing hormone (GnRH) Anterior pituitary Releases LH/FSH

Corticotropin-releasing hormone (CRH) Anterior pituitary Releases ACTH

Somatostatin (GH-RIH or SST) Anterior pituitary Inhibits GH release
Growth hormone-releasing hormone Anterior pituitary Releases GH
(somatocrinin, GHRH)
Prolactin release-inhibiting hormone (PRIH) Anterior pituitary Inhibits PRL release
Dopamine (PRL release-inhibiting Anterior pituitary Releases PRL
hormone, PRIH)
Dopamine (MSH release-inhibiting Anterior pituitary Inhibits MSH release
hormone, MRIH)
Other neurohormones
Arginine vasopressinc (antidiuretic Kidney Water reabsorption
hormone, AVP)
Oxytocin (OXY) Uterus, vas deferens Smooth muscle contraction
Endorphins/enkephalins Pain neurons Desensitizes pain neurons
Thyroid gland
Thyroid hormones

Thyroxine (T4) and triiodothyronine (T3) Most tissues Increase metabolic rate, control
development and differentiation
Calcitonin (thyrocalcitonin, CT)e Bone Prevents resorption caused by parathyroid
hormone

(Continued)
10 Vertebrate Endocrinology

TABLE 1-3 The Mammalian Endocrine System: Major Secretionsa and Actionsdcont’d
Sourceb and Secretions Target Action

Gonads

Ovary
Estrogens (e.g., estradiol) Primary and secondary sexual Stimulate development
structures

Brain Reproductive behavior

Progesterone Uterus Stimulates secretion by uterine glands
Inhibin Anterior pituitary Blocks FSH release
Testis
Androgens (e.g., testosterone) Primary and secondary sexual Stimulates development and secretion
structures
Brain Reproductive behaviord
Inhibin Anterior pituitary Blocks FSH release

Adrenal gland
Adrenal cortex
Aldosterone (A) Kidney Sodium reabsorption; potassium secretion
into urine
Corticosterone (B)/Cortisol (F) Liver, muscle Conversion of protein into carbohydrates
Adrenal medulla
Epinephrine/norepinephrine Liver, muscle Glycogen breakdown to glucose
Parathyroid gland
Parathyroid hormone (parathormone, PTH) Bone Bone resorption or growth

Kidney Calcium reabsorption and phosphate

secretion into urine
Endocrine pancreas Increased glycogen storage

Insulin Liver, Muscle Increased glucose and amino acid uptake

Glucagon
Pancreatic polypeptide
Somatostatin (paracrine substance)
Gastrointestinal system
Adipose tissue Inhibits fat hydrolysis
Liver, adipose tissue Antiinsulin actions
Colon Enhances muscle contraction
Endocrine pancreas Blocks release of pancreatic hormones

Stomach
Gastrin Gastric glands of Stimulates acid secretion
stomach

Ghrelin Brain Stimulates feeding

Small intestine
Secretin
Cholecystokinin (CCK; same as
pancreozymin-cholecystockinin, PZCCK)
Exocrine pancreas Release of basic juice into duodenum
Exocrine pancreas Release of enzymes into duodenum
Gallbladder Contraction to eject bile into duodenum
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates 11

TABLE 1-3 The Mammalian Endocrine System: Major Secretionsa and Actionsdcont’d
Sourceb and Secretions Target Action

Gastrin-releasing peptide Stomach gastrin cells Release of gastrin

Glucose-dependent insulinotropic peptide Endocrine pancreas Release of insulin

(gastric inhibitory peptide, GIP)
Motilin Stomach Stimulates pepsinogen secretion and
gastric motility
Somatostatin (paracrine action) Small intestine Inhibits release of other regulators

Vasoactive intestinal peptide (VIP) Visceral blood vessels Increases blood flow to
Liver
Insulin-like growth factors Many tissues Mitogenic effects
(IGF-I, IGF-II)
Adipose tissue
Leptin Brain Inhibits feeding
Kidney
Erythropoietin Bone marrow Stimulates RBC formation
Renin Renin substrate in blood Produces angiotensin

1,25-dihydroxycholecalciferol Small intestine Stimulates calcium absorption

(1,25-DHC)f
Pineal gland

Melatonin (neurohormone) Brain Controls thyroid, adrenal, and

reproductive events

Immune system
Thymus
Thymosins Lymphocyte-producing tissue Production of lymphocytes
Macrophages/lymphocytes
Interleukin 1 (autocrine/cytocrine) Helper T cell Activation
Interleukin 2 (autocrine/cytocrine) Cytotoxic T cell Activation
a
In some cases, closely related molecular forms may be present and will be discussed at the appropriate time.
b
Alternate names are given in parentheses, along with the most common abbreviation.
c
Some mammals may rely on a different nonapeptide (e.g., lysine vasopressin or phenypressin; see Chapter 4).
d
Secretory cells derived from ultimobranchial gland in mammals become incorporated into the thyroid (see Chapter 14).
e
May require conversion into estrogens within certain brain target cells before effect is observed.
f
Cholecalciferol is made in skin and converted in liver to precursor kidney uses to make 1,25-DHC (see Chapter 14).

orientation of secretory cells is to form folded sheets or
cords of cells as seen in the pituitary gland or the adrenal
cortex. In a few cases, the cells may form a spherical
mass of one cell layer surrounding a fluid-filled space or
lumen. This arrangement is termed a follicle and occurs
in the thyroid gland of all vertebrates and in the
pituitaries of some vertebrates. The lumen provides
a unique storage site for secretions of the follicular cells.
Sometimes, the endocrine cells will be separated into
scattered clumps or islets of a few cells. Mixed islets
containing several secretory cell types are best known in
the pancreas, where they are called the islets of
Langerhans.
Many cells that secrete bioregulators are not histologi-
cally distinct (i.e., do not form discrete tissues) and were
not identified until precise immunochemical techniques
were developed. One of the reasons why it took so long to
identify the sources of gastrointestinal hormones was the
12 Vertebrate Endocrinology

(A) (B)

FIGURE 1-6 Cytology of hormone-secreting cells. (A) Microscopic appearance of a steroid-secreting cell. These adrenocortical cells, from juvenile
salmon, secrete the steroid cortisol exhibit mitochondria with tubular cristae and an abundance of smooth endoplasmic reticulum. (B) A growth-hormone-
secreting cell from the coho salmon (Oncorhynchus kisutch) showing dense secretory granules, well-developed Golgi apparatus, and mitochondria with
plate-like cristae. (Courtesy of Howard A. Bern and Richard Nishioka, University of California, Berkeley.)

FIGURE 1-7 Hormone-secreting cells appear

in many formations. (A) Cords of cells secreting (A) (B)
growth hormone (orange) and gonadotropins
(blue) in a pituitary gland. (B) Islet of insulin-
secreting cells (arrow) embedded within the
darker stained exocrine pancreas. (C) A collection
of follicles (consisting of an epithelium
surrounding a fluid-filled lumen) from a thyroid
gland showing a thin epithelium and pink colloid
(a protein suspension) filling the lumen of the
follicle. (D) Isolated clusters of testosterone-
secreting interstitial cells (arrow) located between
seminiferous tubules in a testis.
(C) (D)
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates 13

TABLE 1-4 Cellular Patterns of Secretion

Secretory Pattern Description Example

Endocrine Product secreted into the blood for transport internally to target tissues Hormones
Exocrine Product secreted into a duct that opens onto an external or internal surface Sweat
Exocytosis Product released from secretory cell via a process essentially the reverse Peptide hormone release
of endocytosis
Merocrine Product secreted without visible damage to the secretory cell (involves exocytosis) Thyroxine secretion

Apocrine Product released by sloughing of “outer” or apical portion of secretory cell Mammary gland milk
Holocrine Product released through cell death and lysis Sebaceous gland secretion
Cytogenous Release of whole, viable cells Spermatozoa

tendency for these secretory types to occur as isolated
endocrine cells mixed in with many other cell types in the
stomach and intestinal walls (see Chapter 12).
Another critical feature of neuroendocrine organization
is the presence of an extensive vascular supply for endo-
crine cells and neurosecretory neurons. Endocrine glands
typically are highly vascularized such that no secretory cell
is far from a blood vessel. The axonal endings of many
neurosecretory neurons terminate collectively in masses of
capillaries to form what is called a neurohemal organ.
These neurosecretory neurons release their neurohormones
into the blood that flows through the neurohemal organ.
Some neurosecretory neurons that release their products
into the cerebrospinal fluid do not form axonal aggregates
at common release sites.
Most regulatory cells employ merocrine secretion,
where secretory products are released by exocytosis with
no damage to the cell. In apocrine secretion, the apical
portion or tip of the cell is sloughed along with stored
secretions, whereas holocrine secretion involves lysis and
death of the secretory cell. These latter two patterns are
more characteristic of exocrine glands such as the
mammary gland (apocrine) or the sebaceous glands of the
skin (holocrine). Cytogenous secretion is the release of
entire cells, such as sperm released from testes or ova
released from ovaries. These secretory patterns are
summarized in Table 1-4.
VI. HOMEOSTASIS
Bioregulatory mechanisms are the bases for controlling all
physiology and behavior. It is through these mechanisms
that homeostatic balance and survival in a harsh and
dangerous environment are possible. Although Claude
Bernard formulated the concept of homeostasis in the 19th
century, it was the American physiologist Walter B.
Cannon who in 1929 coined the term homeostasis to
describe balanced physiological systems operating in the
organism to maintain a dynamic equilibriumdthat is,
a relatively constant steady state maintained within certain
tolerable limits. In Cannon’s words:1
When we consider the extreme instability of our bodily structure,
its readiness for disturbance by the slightest application of
external forces and the rapid onset of its decomposition as soon as
favoring circumstances are withdrawn, its persistence through
many decades seems almost miraculous. The wonder increases
when we realize that the system is open, engaging in free exchange
with the outer world, and that the structure itself is not permanent
but is being continuously broken down by the wear and tear
of action, and is continuously built up again by processes of
repair.
The constant conditions which are maintained in the body
might be termed equilibria. That word, however, has come to have
fairly exact meaning as applied to relatively simple physico-
chemical states, in closed systems, where known forces are
balanced. The coordinated physiological processes which main-
tain most of the steady states in the organism are so complex and
so peculiar to living beingsdinvolving, as they may, the brain and
nerves, the heart, lungs, kidneys and spleen, all working cooper-
ativelydthat I have suggested a special designation for these
states, homeostasis. The word does not imply something immobile,
a stagnation. It means a conditionda condition which may vary,
but which is relatively constant.
Cannon’s original formulation of the homeostatic mecha-
nism emphasized the maintenance of blood parameters
such as osmotic pressure, volume, hydrostatic pressure, and
levels of various simple chemicals such as calcium,
1. Cannon, W.B., The Wisdom of the Body, W.W. Norton, New York,
1932, pp. 20, 24.
14
sodium, and glucose. Cannon’s viewpoint can be expanded
to include all manner of physiological bioregulation at the
level of the organism as well as at the molecular and
cellular level. The concept of allostasis was developed to
explain the complex role of bioregulators in integrating the
response of many organ systems to changes in the envi-
ronment (see Chapter 8).
When attempting to comprehend physiological systems,
it is helpful to employ simplified models that simulate
the various components of the system in a way that is easy
to grasp and at the same time provide insights into how
the system works as well as predictions on how it will
respond to disturbances. In the following paragraphs, we
will consider a very simple model of a basic bioregulatory
mechanism operating for all physiological systems and
provide some insight on how to use this model to understand
complicated, integrated endocrine systems such as those
discussed in later chapters.
A. A Homeostatic Reflex Model
In this model, information (I) is any stimulus that can
provide quantitative or qualitative cues detectable in
some way by the system. The basic model is depicted in
Figure 1-8. The information is detected by a receptor (R)
or transducer of some sort that translates (transduces) this
information into the language of the bioregulatory system.
For example, the opening of voltage-gated sodium channels
may allow sodium ions to enter a neuron, depolarizing the
cell membrane and inducing an action potential that in turn
I I´
R C
Output
Negative
feedback E of a hormone decreases below its set point, it stimulates
loop
Change in
Effect
the system
FIGURE 1-8 A homeostatic model. This simple homeostatic mecha-
nism could represent a single cell as well as an endocrine or neurocrine
unit. The mechanism involves the detection of information (I) by
a receptor (R) that converts the information into biologically relevant cues
or input (I0 ) and transmits this to the controller (C). The controller
compares the input to a programmed set point and makes physiological
adjustments as needed by producing output. This output travels by intra-
cellular pathways (intracrines), neural axons (neurocrines), blood
(hormones), or even extracellular fluid (autocrines/paracrines) to effectors
(E) that in turn cause a change in the system that also feeds back via the
same or different receptors to alert the controller that a change has
occurred. Because this type of feedback drives the system toward the set
point, it is called negative feedback.
Vertebrate Endocrinology
causes a nerve impulse to be generated. The transduced
information is now called input (I0 ) and is translocated
to an integrating center called the controller (C). The
controller uses a preprogrammed set of instructions to
compare the input with a set point and determines whether
any adjustments are warranted. If the controller ascertains
adjustments are needed to maintain or regain homeostatic
balance, it will direct a message called output (O) (e.g., the
nerve impulse and release of a neurotransmitter) to one or
more effectors (E) (e.g., a postsynaptic muscle cell) which
will perform some specific action (effect, Ef) which, in
turn, will bring about corrective changes in the system
(contraction of the muscle cell). The responsiveness of the
controller may be influenced by input received from other
homeostatic bioregulators. These additional inputs may
enhance or reduce the output of the controller through
altering its sensitivity to other input or by adjusting the
set point.
Corrective changes signaled in response to output from
the controller will alter the nature of the information
originally perceived by the receptors. If the response has
been sufficient and appropriate, the controller will be
notified immediately by new information detected by
receptors through a pathway called feedback. If the
response was insufficient, the controller may increase its
output to elevate the effector response. If an overcorrection
or overshoot has occurred, the controller will alter its
output accordingly and may even generate new output to
other effectors to bring the system into line with the pre-
programmed set point. Therefore, the set point represents
the optimal physiological condition. The feedback loop that
drives a physiological system toward the preprogrammed
set point is called negative feedback. Any disturbance
regardless of the direction of the disturbance (i.e., “up” or
“down”) causes a homeostatic reflex to be activated to
maintain homeostasis. For example, when the blood level
mechanisms that will increase its blood level back to the set
point. Similarly, if the level of the hormone is greater than
the set point, the mechanisms for its secretion will be
decreased or inhibited by the controller until the blood level
falls back to the set point. In either case, this would be
considered negative feedback because it drives the system
toward the set point from either above or below.
Consider a controlled-temperature room as a physical
model of a simple control system similar to what has been
described for a biological system. The programmable
thermostat represents both the receptor and controller
components; an air conditioner and a heater are the effec-
tors. Mechanical deformations produced in a bimetal strip
(receptor) exposed to the air temperature (information) of
the room are transduced into electrical current (input). The
controller compares this input with the preprogrammed
temperature (set point) and electrically turns on or off
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates
(output) the appropriate effector to maintain a constant
temperature (homeostasis). The new air temperature will be
detected by the same receptor and new input will be sent to
the controller that will continue to make adjustments up or
down as needed to drive the system toward the set point
(negative feedback).
Under some conditions, feedback may drive a system
away from the preprogrammed condition, usually to
a higher level but sometimes to a lower level. Such a
feedback loop is called positive feedback, and it drives
a system to a different level of activity. Positive feedback is
invoked where a rapid change is required, may be associ-
ated with an emergency type response, or might be
responsible for short-term adaptations to complete a series
of changes. The rapid influx of sodium during generation of
an action potential, the physiological stress response
(Chapter 8), certain events during ovulation, and the
induction of labor causing birth in mammals (Chapter 10)
are all examples of events that employ positive feedback. In
general, positive feedback is important for short-term
events but is detrimental over longer time periods and can
lead to disease or even the death of the animal if it persists.
In contrast, long-term negative feedback generally is
advantageous to long-term survival as it helps maintain
homeostasis in the face of environmental or internal
changes. Negative feedback is the most common type of
feedback in physiological systems.
In certain instances, changes in a regulated variable are
anticipated through feedforward regulation, which
accelerates homeostatic responses and minimizes fluctua-
tions in the regulated variable. For example, the regulation
of internal body temperature involves a classical negative-
feedback loop based on the temperature of the blood
flowing to the brain. However, changes in body surface
temperature before internal temperatures are affected can
send additional neural input to the brain that begins making
appropriate adjustments in temperature production and
conservation or dissipation of heat to ward off changes in
internal body temperature predicted by the input from the
skin. Secretions invoked by the digestive system following
appearance of glucose in the small intestine result in
secretion of insulin from the endocrine pancreas even
before blood sugar has become elevated, the normal
homeostatic stimulus causing insulin release. Thus,
increased levels of insulin appear ready to direct glucose
entering the blood from the intestine into cells for use or
storage. These are examples of feedforward regulation.
To apply this homeostatic reflex model to any bio-
regulatory mechanism, one must ask a series of simple
questions. First of all, on what information does the system
cue? What are the receptors and where are they located?
What sort of input is generated by this stimulus and how is
it conducted to the controller? What is the controller and
where is it located? What is the set point? What sort of
15
output is generated? What are the effectors and what effects
are produced? What changes in the system result and how
does feedback occur? Is there negative, positive, or feed-
forward regulation involved?
When examining chemically regulated systems, you
will soon discover that complicated responses involve the
integration of many different simple homeostatic reflexes.
For example, the “controller” for one system may actually
be the “effector” of another homeostatic reflex, and there
may be pathways that modulate the responsiveness of
a controller or effector to other stimuli. An excellent
example of the integration of individual reflexes is the
neuroendocrine reflex.
A typical vertebrate neuroendocrine reflex is repre-
sented by the adrenal endocrine axis in Figure 1-9. The
liver cell can be considered an effector (target cell) whose
activity is regulated by a steroid hormone (e.g., cortisol)
from the adrenal cortex. This would make the adrenal
cortex the controller, but the adrenal cortex is also an
effector for the anterior pituitary that controls its secretion
of cortisol through output of a tropic hormone, cortico-
tropin or ACTH. In turn, the anterior pituitary is also an
effector for a neurohormone (corticotropin-releasing
hormone, CRH) from the hypothalamus (arbitrarily labeled
the main controller in this diagram). Only the major or
primary feedback loop of cortisol is shown, but other
feedback loops may be operating in this system (see
Chapters 4 and 8). In this neuroendocrine reflex, we have
indicated that the hypothalamic controller receives infor-
mation via the blood but it also can be affected by infor-
mation accumulated through a variety of receptors
associated with other reflexes or from the environment.
Two neural reflex loops are shown, each with its own
receptor and controller that might send modulating input
to the hypothalamic controller, altering the set point or
telling the hypothalamus to ignore the set point altogether.
In spite of the apparent complexity of this neuroendocrine
reflex as compared to our basic model, one simply asks the
same series of questions given above for each level in the
system until an understanding is achieved of the integrated
whole.
B. Endocrine Disruption of Homeostasis
Traditionally, clinical endocrinology has dealt with disor-
ders of the endocrine system that involve a disruption of
homeostasis. Because of the broad actions of hormonal
chemical regulators, homeostasis can be profoundly
affected by endocrine imbalances. A listing of some well-
characterized endocrine disorders is provided in Table 1-5.
Many disorders are discussed in later chapters after the
normal endocrine physiology is described.
A recent focus for endocrinologists is the potential for
disruption of endocrine functions in natural ecosystems
16
FIGURE 1-9 A complex neuroendocrine
homeostatic system. This mechanism External R NC
stimulus
involves the interaction of neurohormones
from the brain (controller), tropic hormones Internal R
from the pituitary (E2), and hormones from stimulus
a variety of endocrine glands to control more
complicated events. Note that multiple
receptors, multiple effectors (targets), and
multiple feedback loops may occur.
Multiple
effectors
caused by the presence of discarded chemicals in our
surroundings, exposures at work, or daily contact such as
through the use of pharmaceuticals, plastics, certain deter-
gents, personal care products, and food. Initially, they were
called EDCs because we became aware of them through
their disruptive effects on vertebrate reproduction and
thyroid function. Some prefer more general names such as
endocrine-active chemicals (EACs) because they may act as
disrupters or simple mimics of hormones. Still others prefer
to designate them as part of a variety of chemicals called
“emerging contaminants” because we now recognize
a much broader range of effects in animals beyond the
endocrine system. We use the acronym EDC because our
focus deals primarily with the endocrine system. These
EDCs are produced by human activities (i.e., they are
anthropogenic) and can mimic natural bioregulators; they
can prevent their synthesis, transport, or normal actions or
alter their rates of metabolism and/or excretion. EDCs
represent a wide variety of compounds of diverse origins
Vertebrate Endocrinology
I´
Brain
I´
Output =
Neurohormone
A B
E1 E2
Effect Tropic
hormone
E3
Hormone
E1
Effect
(Table 1-6). For example, some of them are pesticides,
including insecticides (e.g., DDT and its metabolite DDE),
herbicides (e.g., atrazine, glyophosate), and fungicides
(e.g., vinclozolin). Others are industrial or mining byprod-
ucts such as heavy metals, dioxins, and PCBs. Estrogenic or
anti-androgenic (feminizing) chemicals such as phthalates,
nonylphenols, and bisphenyl A (BPA), leach from a variety
of plastics used in food and beverage packaging, dental
sealants, aerosol sprays, latex paints, cosmetics and personal
care products, and many other products we use everyday.
Phytoactive chemicals are endocrine-disrupting chemicals
produced in plants that find their way into animal systems
either through diet or as a result of industrial activities
(e.g., pulp and paper mill effluents dumped into rivers).
Humans excrete natural hormones as well as prescription
and non-prescription pharmaceuticals taken for therapeutic
purposes which pass to wastewater treatment plants and can
concentrate in aquatic systems, affecting wildlife as well as
the drinking water of downstream human communities.
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates 17

TABLE 1-5 Clinically Relevant Endocrine Disorders

Disease Description

Acromegaly Inappropriate and continued secretion of growth hormone by a tumor of pituitary cells which leads to
soft tissue swelling and hypertrophy of the skeletal extremities (usually in the third or fourth decade).
Addison’s disease Adrenocortical insufficiency resulting from a deficient production of glucocorticoids and/or mineralo-
corticoids due to a destruction of the adrenal cortex.
Cretinism Characterized by a permanent neurological and skeletal retardation and results from an inadequate
output of thyroid hormone during uterine and neonatal life; may be caused by iodine deficiency, thyroid
hypoplasia, genetic enzyme defects, or excessive maternal intake of goitrogens.

Cushing’s disease
Cushing’s syndrome
Diabetes insipidus
Diabetes mellitus
Diabetes mellitus
Type I (insulin-dependent)
Hypercortisolism resulting from the presence of small pituitary tumors which secrete ACTH leading to
excess production of cortisol by the adrenals.
The circumstance of glucocorticoid excess without specification of the specific etiology; it may result
from endogenous causes but is more commonly iatrogenic (physician-induced).
A deficient secretion of vasopressin which is manifested clinically as diabetes insipidus; it is a disorder
characterized by the excretion of an increased volume of dilute urine.
A disease characterized by a chronic disorder of intermediary metabolism due to a relative lack of
insulin which is characterized by hyperglycemia in both the postprandial and fasting state (see also
types I and II diabetes mellitus).
The form of diabetes that usually appears in the second and third decades of life and is characterized by
a destruction of the pancreas B cells; this form of the disease is normally treated with daily administra-
tion of insulin.

Diabetes mellitus The form of diabetes often arising after the fourth decade, usually in obese individuals; this form of the
Type II (insulin-independent) disease does not normally require treatment with insulin.
Feminization Feminization of males, usually as manifested by enlargement of the breasts (gynecomastia) which can
be attributed to an increase in estrogen levels relative to the prevailing androgen levels.
Froehlich’s syndrome A condition usually caused by craniopharyngioma (a tumor of the hypothalamus) which results in
a combination of obesity and hypogonadism; sometimes termed adiposogenital dystrophy
Galactorrhea The persistent discharge from the breast of a fluid that resembles milk and that occurs in the absence of
parturition or else persists postpartum (4e6 months) after the cessation of nursing.
Gigantism This condition appears in the first year of life and is characterized by a rapid weight and height gain;
affected children usually have a large head and mental retardation; to date no specific endocrine abnor-
malites have been detected.
Goiter Goiter may be defined as a thyroid gland that is twice its normal size; endemic goiter is the major
thyroid disease throughout the world. Goiter is frequently associated with a dietary iodine deficiency;
in instances of sporadic goiter it may occur as a consequence of a congenital defect in thyroid hormone
synthesis.
Grave’s disease An autoimmune disease characterized by the presence in the serum of long-acting thyroid stimulator
(LATS) that is an antibody that activates the receptor for TSH. Grave’s disease is the most common cause
of thyrotoxicosis.
Gynecomastia Abnormal breast enlargement which may occur in males during puberty.
Hermaphroditism True hermaphroditism is defined as the presences of both testicular and ovarian tissue in the same
individuals; pseudohermaphroditism is a discrepancy between gonadal and somatic sex.
Hirsutism An increase in facial hair in women which is beyond that cosmetically acceptable; this condition may
be associated with a number of masculinizing disorders including Cushing’s syndrome, congenital
adrenal hyperplasia, and polycystic ovary syndrome.
Hyperaldosteronism An inappropriate secretion of aldosterone. It can occur as a primary adrenal problem (e.g., adrendal
tumor) or can be secondary to other metabolic derangements that stimulate its release; it is often char-
acterized by inappropriately high levels of plasma renin.

(Continued)
18 Vertebrate Endocrinology

TABLE 1-5 Clinically Relevant Endocrine Disordersdcont’d

Disease Description

Hyperparathyroidism
Hypoparathyroidism
Klinefelter’s syndrome
Inappropriately high secretion of PTH leading to hypercalcemia. Frequently associated with the
hyperparathyroidism is a metabolic bone disease characterized by excessive bone calcium reabsorp-
tion; frequently attributable to an adenoma of the parathyroid gland.
Inappropriately low secretion of PTH, leading to hypocalcemia; the disease is either idiopathic or iatro-
genically induced.
Typically characterized by male hypogonadism; the presence of extra X chromosomes is likely the
fundamental underlying etiological factor. It is characterized by varying degrees of decreased Leydig
cell function and seminiferous tubule failure.

Myxedema Hypothyroidism clinically manifested by the presence of a mucinous edema; the disease may appear at
any time throughout life and is attributable to disorders of the thyroid gland or to pituitary insufficiency.
Osteomalacia A bone disease in adults characterized by a failure of the skeletal osteoid to calcify; it is usually caused
by an absence of adequate access to vitamin D.
Polycystic ovary syndrome A complex of varying symptoms ranging from amenorrhea to anovulatory bleeding, often associated
(PCOS) with obesity and hirsutism. The term denotes an absence of ovulation in association with continuous
stimulation of the ovary by disproportionately high levels of LH.
Premature ovarian failure or Patient typically presents with high FSH levels, low estrogen levels, and amenorrhea. Many potential
insufficiency causes include genetic disorders, autoimmune disease, smoking, and ovarian resistance. Secondary
ovarian failure is caused by the failure of the pituitary gland to secrete FSH.

Pseudohypoparathyroidism
Rickets
Turner’s syndrome
Zollinger-Ellison syndrome
A familial disorder characterized by hypocalcemia, increased circulating levels of PTH, and a peripheral
unresponsiveness to the hormone; afflicted individuals frequently are of short stature, with mental
retardation and short metacarpals and/or metatarsals.
A failure in the child of the skeletal osteoid to calcify; it is usually caused by an absence of adequate
amounts of vitamin D; it is characterized by a bowing of the femur, tibia, and fibulas
A condition present in females with a 45, XO chromosome pattern (i.e., complete absence of the X
chromosome). The XO individual is typically short with a thick neck and trunk and no obvious
secondary sex characteristics.
Tumors of the pancreas which result in excessive secretion of gastrin; the afflicted subject has recurrent
duodenal ulcers and diarrhea caused by hypersecretion of gastric acid.

Pharmaceutical compounds with hormonal activity, such as
the birth control steroid ethynylestradiol (EE2), or neuro-
active chemicals, such as fluoxetine, are designed to resist
degradation and hence may be very persistent in the
environment.
Conventional sewage treatment systems are not designed
to remove all of these EDCs (and in some cases may
increase their potency), and even small concentrations
(nanograms/liter) may produce effects in wildlife. Many of
these compounds have been shown in clinical, laboratory,
and field studies to be estrogenic (e.g., DDT, 4-nonylphenol,
BPA, EE2), androgenic (e.g., trenbolone), antiandrogenic
(e.g., vinclozolin, phthalates), anti-thyroid (e.g., PCBs,
perchlorate), or anti-adrenal (e.g., cadmium). Although
most of these compounds end up in biosolid wastes, suffi-
cient endocrine and neuroactive compounds, for example,
may pass with the processed sewage effluent into freshwater
and estuarine environments, where effects on reproduction
and behavior of fishes and other wildlife have been
described. The nanogram or microgram/liter levels of EDCs
in wastewater effluents are well below the standardized
“safe” toxicity levels determined by traditional toxicology.
Unfortunately, biological receptors can detect natural bio-
regulators and bioregulator mimics at much greater dilutions
than traditional chemistry.
Increased incidences of breast, prostate, and testicular
cancer and reduced sperm counts have been reported in
human populations in developed countries. Decreases in
the proportion of live male to live female births have
occurred since the 1990s, although the prior ratio was
consistent for the previous 500 years. Puberty has been
occurring at progressively earlier ages, especially in the
past two decades. These are, of course, correlative changes
only; the causes of these changes are not established and
could be very complex in nature. However, increased inci-
dences of abnormal reproductive development, especially
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates 19

Europe, Asia, and North America has been attributed

TABLE 1-6 Classification of Some Known Endocrine- directly to the presence of mixtures of estrogenic
Disrupting Chemicals (EDCs) substances of human origin (see Figure 1-10). Because
By usage hormone mimics add to and hormone inhibitors detract
Propellants/surfactants (e.g., nonylphenols) from natural bioregulators already present, there is theo-
Plant substances (e.g., genistein) retically no level for any EDC that may not have conse-
Personal care products (e.g., phthalates, parabens) quences in natural populations. This concept of “no safe
Pesticides (e.g., DDT, methoxychlor, atrazine, Roundup)
level” is in marked contrast to traditional toxicology, which
Pharmaceuticals (e.g., diethylstilbestrol, ethinylestradiol,
antidepressants) could readily define a “safe” level when using death or
Plasticizers (e.g., phthalates, bisphenol A) disease induction as evidence of toxicity.
Phytoestrogens (e.g., genistein) Endocrine-disrupting chemicals may be additive in
By chemistry producing effects in animals when they all operate through
Alkylphenol ethoxylates and derivatives (includes the same mechanism (such as by binding to the same
nonylphenols) receptor). For example, BPA, nonylphenol, EE2, and the
Dioxins natural hormone estradiol all bind to the estrogen receptor
Heavy metals
and produce estrogenic effects if present in sufficient
Polychlorinated biphenyls (PCBs)
Perchlorate amounts. However, it has been well documented that
Phthalates mixtures of these chemicals are estrogenic even when each is
Steroids present at a dose that by itself will not produce an estrogenic
By endocrine-disrupting actions effect if the total amount of estrogen is sufficient to stimulate
Androgenic enough receptors (see Figure 1-11). Even mixtures of
Anti-adrenal chemicals working through different pathways (e.g., PCBs
Anti-androgenic and dioxins) can produce additive effects on reproduction.
Anti-estrogenic
Timing of the exposure to EDCs may be critical. The
Anti-thyroid
Estrogenic effects of a given EDC might appear during gamete prep-
Obesogenic aration, embryonic or postembryonic development, sexual
maturation, or breeding. It might cause a change of sex,
reduce survival, reduce fertility, prevent normal reproduc-
tion, or accelerate senescence. The presence of “normal”
in newborn males, are correlated directly with exposures to levels of estrogenic phthalates in the urine of pregnant
estrogenic compounds as are some cases of precocial women as well as the consumption of vegetarian diets
puberty in girls. The discovery of feminized fishes in during pregnancy are correlated with increased incidence
wastewater-effluent-dominated streams and estuaries in of abnormal genitalia in males at birth. Exposure of

FIGURE 1-10 Intersex gonad from white

sucker (Catostomus commersoni). The left
panel illustrates the normal ovary from fish at
a reference site above a wastewater treatment
Ovarian plant (WWTP). The middle panel shows
tissue ovarian tissue to the left and spermatogenetic
tissue to the right in an intersex gonad of a fish
collected downstream of the discharge from
a WWTP. To the right is a section through
a normal testis from the reference site.
Intersex fish also produce the female estrogen-
dependent protein vitellogenin. (Courtesy of
Alan Vajda, University of Colorado, Denver.)

Spermatogenetic
Tissue

Normal Ovary Intersex Gonad Normal Testis

20 Vertebrate Endocrinology

or decades later. Epigenesis is the progressive change in

gene transcription that makes differentiation of an early
embryo into multiple cellular types and organs possible.
Estrogenicity

Gene transcription is controlled by patterns of methylation

Threshold
Dose
1 ng 10 µg 0.7 ng Mixture
E2 BPA EE2
FIGURE 1-11 Additive effect. The additive effect of a mixture of
estrogenic chemicals working through the estrogen receptor but with very
different affinities for the receptor. Each chemical by itself at the dose
indicated has some stimulatory ability but not enough to reach the threshold
dose necessary to get an overt effect. However, when all three are present in
a mixture, their effects are additive and an estrogenic effect occurs.
pregnant women to thyroid inhibitors such as PCBs or
perchlorate could alter development of the nervous system
and induce mental deficiencies (see Chapter 6). Studies on
achievement of children exposed to significant levels of
PCBs during development have demonstrated that children
of mothers exposed to PCBs through their diet while
pregnant performed poorly on intelligence tests as
compared to control populations.
1. Epigenetic Effects During Development and
Transgenerational Epigenetic Effects of EDCs
Embryonic exposure to certain EDCs may produce epige-
netic effects in an individual that do not appear until years
of the DNA or the chemical alteration of histone proteins in
chromatin that prevent genes from being expressed.
Demethylation and the addition of acetyl groups (acetyla-
tion) to histone proteins via the enzyme histone acetyl-
transferase (HAT) allows genes to be transcribed. Thus,
the pattern of DNA methylation, for example, becomes
established in a certain somatic cell type during develop-
ment and remains the same in that cell type for the life of
the animal. In the somatic cells of the body, some of these
genes may be active all of the time. Some genes may be
active early whereas others are not activated until later in
life. The basic methylation and histone acetylation patterns
of the zygote are retained in the resulting germ cells that
reside in the gonads. When eggs or sperm are produced,
that pattern is retained to direct early development of a new
individual following fertilization of an egg. The ability of
a cell or an organism to inherit different phenotypes asso-
ciated with DNA methylation and histone acetylation,
without any change in the sequence of the DNA in the gene
being transcribed, is referred to as epigenetics.
During development, there are distinct periods when
a general demethylation of the DNA occurs followed by
remethylation (Figure 1-12). If the pattern of methylation is
changed accidentally or by exposure to environmental
chemicals during these periods, abnormal patterns of gene
activation or repression may result in all descendants of that
cell type and manifest later in the life of that individual as

FIGURE 1-12 Epigenetic program- Paternal

ming. In this example, a general period of Active DNA demethylation
DNA demethylation takes place in the Hypomodified histones
testes when sperm are made followed by Maternal
remethylation. After fertilization, deme- Gametes Methylated DNA
thylation allows for functioning of genes Modified histones
necessary for very early development
following fertilization. A later period of
methylation and histone modification is Passive
shown. (Adapted with permission from DNA demethylation
De novo
Morgan, H.D. et al., Human and Molec- methylation Gametogenesis Preimplantation
ular Genetics, 14, R47eR58, 2005.) development
Epigenetic De novo
Reprogramming DNA methylation
Cycle

DNA
demethylation

Primordial Inner cell mass (ICM)

germ cells Methylated DNA
(PCGs) Modified histones
Chapter | 1 An Overview of Chemical Bioregulation in Vertebrates
various kinds of disorders including cancer. The exposure
of mammalian embryos to certain estrogenic (feminizing)
and anti-androgenic (demasculinizing) chemicals has
influenced the incidence of reproductive cancers when
those offspring become adults and age. Studies of labora-
tory rodents exposed while in the uterus demonstrate that
these effects are permanent and are passed on to their
offspring over several generations through epigenetic
mechanisms.
BOX 1A Histone Acetylation and Hormone-Sensitive
Cancer
Acetylation or deacetylation of lysine residues on histone
proteins is generally thought to increase or decrease gene
transcription, respectively, and histone acetylation/deacety-
lation is often an important mechanism in hormone action,
especially for steroid hormones. The enzymes responsible for
acetylating and deacetylating histonesdhistone acetyl-
transferases and histone deacetylases (HDAC)dare becoming
increasingly important targets for therapies to treat hormone-
sensitive tumors. In particular, HDAC inhibitors have shown
promise in causing suppression of tumor growth in prostate,
ovarian, and breast cancer. Although the precise mechanisms
underlying HDAC inhibitor suppression of tumor growth
remain an active area of investigation, HDACs are overex-
pressed in some hormone-sensitive tumors and may be
involved in the invasion of blood vessels (angiogenesis) that
accompanies the growth of solid tumors found in breast and
prostate cancer patients.
2. Broader Implications of EDCs
Most studies of EDCs have been focused on vertebrates, but
many invertebrate species are sensitive to many of the same
EDCs because they exhibit many of the same biochemical
pathways and mechanisms. Chemical bioregulatory and
communication mechanisms are determined by similar
genes, and these ancient mechanisms have been subjected
to thousands of manmade chemicals within just a few
decades. Thus, systems that evolved over millions of years
are being subjected to significant levels of chemicals that
can interfere with or mimic critical pathways and processes
necessary for reproduction and survival. And this is
happening in a very short time. There are surprisingly many
parallels in bioregulation with respect to the specific
compounds involved and their receptors between the
millions of known invertebrates and the relatively small
number of vertebrate animals. Already, numerous examples
of endocrine disruption have been described in annelids
(e.g., earthworms), mollusks (e.g., snails), echinoderms
(e.g., sea stars), and arthropods (e.g., insects and crusta-
ceans). No one knows yet the actual impact of EDCs on
21
natural ecosystems, but the potential for devastating effects
is there. Recognition of the real and potential consequences
of this unique pollution problem has led to recent world-
wide attention and considerable controversy. The economic
importance of these compounds and the potential financial
consequences of these disruptive observations versus the
health of wildlife and human populations provide a focus
for the controversy. Certainly, endocrine disruption and its
consequences for the future of life on Earth should be
a major focus of comparative and clinical endocrinologists
both now and in the future.
VII. ORGANIZATION AND GOALS
FOR THIS TEXTBOOK
This book is organized along rather traditional lines with an
emphasis on the hypothalamusepituitary axes followed by
considerations of the regulation of metabolism and calcium
physiology. Chapter 2 describes the tools used by endo-
crinologists of the past and present to provide the reader
with a background in how we have learned what we know
and hope to learn from future studies. Chapter 3 introduces
most of the bioregulators discussed in this book, their
chemistry, their mode of synthesis, their mechanism of
action, and how they are metabolized or excreted. Orga-
nization and functioning of the mammalian systems are
discussed in Chapter 4 (Hypothalamus and Pituitary),
Chapter 6 (Thyroid), Chapter 8 (Adrenal), Chapter 10
(Reproduction), and Chapter 12 (metabolism). Because all
of the terminology is primarily based on the mammalian
systems, the endocrine systems of the rest of the vertebrates
and discussion of their evolution follow each mammalian
chapter to provide a complete treatment of the vertebrates
(Chapters 5, 7, 9, 11, and 13). A discussion of calcium
regulation in all vertebrates can be found in Chapter 14.
As each endocrine gland or endocrine axis is discussed,
the reader will find not only a discussion of the anatomy
and detailed chemical events that shape our physiology and
behavior but also descriptions of some of the classical
endocrine disorders related to normal endocrine events.
Additionally, current information on EDCs that target these
same systems in wildlife and humans will be provided.
Each chapter concludes with suggested readings providing
the documentation behind information found in the chap-
ters as well as in-depth treatments beyond the scope of this
book for those who might want to pursue topics further.
STUDY QUESTIONS
1. How did you define endocrinology and endocrine
system prior to reading this chapter? Has your view
changed since reading this chapter? In what way(s)?
2. Name and define the general categories of bioregulators.
3. How is the endocrine system organized?
Another random document with
no related content on Scribd:
cresceva poco o spesso addirittura non scemava? Potremo noi
pensare a raffinar questo gran blocco greggio che è la civiltà
moderna, se gli uomini continueranno a pullulare da ogni parte? O
non bisognerà allora continuare a inventar macchine, a saccheggiar
territori in fretta e furia, a rovesciar tutti i limiti, a dire che è progresso
il far più presto, anche facendo peggio?
Delle grida interruppero il discorso. Dei passeggeri credevano di
scorgere Genova. Un cameriere porse il suo conto al Rosetti che
partì con lui.
Vedendo nelle terze classi i bagagli degli emigranti accatastati nel
mezzo, mi ricordai di Orsola e delle sue lettere: ma Orsola con mille
discorsi, pianti e lai mi disse che le lettere dovevano avergliele
rubate, perchè non c’erano più nella valigia. Le voltai indispettito le
spalle, certo ormai che avevo avuto a fare con una isterica inquieta e
piena di fole.
— Purchè le sue storie non vadano ad arricchire la letteratura
dell’emigrazione! — pensai.
Tornato sul ponte, sentii la bella genovese che in un crocchio diceva
con disprezzo:
— Sapete quanto ha dato di mancia? Duecento lire!
Il gioielliere era sdegnato; gli altri non si pronunciavano; solo la
moglie del dottore di San Paolo:
— Se però — diceva un po’ timidamente — avessimo dato tutti in
proporzione!
Ma la genovese inviperita:
— E il bel regalo, lo ha ricevuto non è vero, anche lei? Bello come il
mio!
Ahimè! la leggenda della signora era stata ben caduca. Ma in quella
sopraggiunse l’Alverighi, sbuffando:
— Come si respira male, nel Mediterraneo. Appena si esce
dall’Atlantico si sente il chiuso e lo stantio, non è vero?
Poi ci additò in lontananza i monti della Liguria e le piccole case.
— E pensare — disse — che ognuno di quei miserabili che stentano
la vita su quei dirupi potrebbe diventar milionario, se emigrasse in
Argentina! L’Europa è piena di imbecilli!
Gli risposi ridendo che non sarebbe poi una così bella cosa se tutti
diventassero milionari, perchè allora chi ci lustrerebbe ancora le
scarpe? Ma non mi diè retta e:
— Abbiamo discorso per due settimane di cose inutili, Ferrero; vuol
che facciamo un piccolo discorso serio? Vuol che i suoi figli almeno
un giorno siano milionari? Compri terre nella provincia di Mendoza,
dove le abbiamo noi. O nella provincia di Cordova....
E mi spiegò diverse speculazioni, per conchiudere:
— Compri, compri; questo è il momento; e poi non ci pensi più.
Arricchirà dormendo.
E avendogli io risposto che non me ne importava:
— Si è convertito anche lei al Vedantismo? — disse ridendo. —
Quanto a me io voglio farli, i miei cento milioni: se no che ci starei a
fare al mondo?
Intanto in lontananza un mucchio bianco era spuntato davvero —
Genova; a poco a poco ingrandì, si chiarì sotto il sole che squarciava
le nuvole. Incominciarono gli estremi saluti: cordiali e quasi intimi tra
me, mia moglie, il bambino, il Cavalcanti, l’Alverighi, l’ammiraglio, la
signora Feldmann, il signor Vazquez, il Rosetti: più contegnosi e
sostenuti con gli altri passeggeri. Tra questi saluti comparvero a un
tratto il signore e la signora Yriondo; lui pallido, magro, febbricitante
ancora.
— Cose da pazzissimi, un assassinio in regola — borbottò il dottore.
Ma la signora era fiera di poterci mostrare i miracoli della «Christian
Science», e ci disse che uscendo di letto suo marito compiva un atto
di energia che fugherebbe ancora più lontano la mortale illusione
della malattia.
Ben presto fummo in vista del porto; il vapore rallentò la sua corsa;
entrammo; da lungi apparve lo scalo, nero e gremito di persone. Ci
avvicinammo a poco a poco; tra lo scalo e il vapore incominciarono i
saluti, i cenni, l’agitare dei fazzoletti: la nave iniziò la manovra
dell’attreccamento. Ormai dalle sponde gremite della nave parlavano
tutti con gli aspettanti, chiedevamo e davamo notizie del viaggio,
degli amici, dei parenti. Finalmente la nave si fermò e le scale furono
poste; le autorità e i funzionari della compagnia vennero a bordo; gli
ultimi saluti furono scambiati.
Mi recai a salutare il capitano Mombello e a ringraziare lui e il
rappresentante del Lloyd Italiano di tutte le cortesie ricevute. Poi
scendemmo insieme: la mia signora, il bambino e il signor Rosetti.

FINE.
 Opere di Guglielmo Ferrero:

Grandezza e Decadenza di Roma.

Vol. I: La Conquista dell’Impero L. 5 —

Vol. II: Giulio Cesare 5—
Vol. III: Da Cesare ad Augusto 5—
Vol. IV: La repubblica di Augusto 3 50
Vol. V: Augusto e il Grande Impero 3 50

Roma nella cultura moderna. Discorso tenuto in

Campidoglio il 21 aprile 1910, commemorando il
Municipio il «Natale di Roma» 2—
In memoria di Cesare Lombroso (1910).
Conferenza, con due ignorati scritti di Lombroso 2—

Cronache criminali italiane [con Scipio Sighele]

(1896). Con 12 ritratti 4—
 Nota del Trascrittore

Ortografia e punteggiatura originali sono state

mantenute, correggendo senza annotazione minimi
errori tipografici.
Copertina creata dal trascrittore e posta nel pubblico
dominio.
*** END OF THE PROJECT GUTENBERG EBOOK FRA I DUE
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