4

Drugs Affecting the

Endocrine System
chapter 22
Physiology of the Endocrine System
Objectives
AFTER STUDYING THIS CHAPTER, THE STUDENT WILL BE ABLE TO:
1. Discuss the relationship between the endocrine
system and the central nervous system.
2. Describe general characteristics and functions
of hormones.
3. Differentiate steroid and protein hormones in
relation to site of action and pharmacokinetics.
OVERVIEW
The endocrine system participates in the regulation of es-
sentially all body activities, including metabolism of nutri-
ents and water, reproduction, growth and development, and
adapting to changes in internal and external environments.
The major organs of the endocrine system are the hypothal-
amus, pituitary, thyroid, parathyroids, pancreas, adrenals,
ovaries, and testes. These tissues function through hormones,
substances that are synthesized and secreted into body fluids
by one group of cells and have physiologic effects on other
body cells. Hormones act as chemical messengers to transmit
information between body cells and organs. Most hormones
from the traditional endocrine glands are secreted into the
bloodstream and act on distant organs.
In addition to the major endocrine organs, other tissues
also produce hormones. These endocrine-like cells intermin-
gle with nonendocrine cells in various organs. Their hor-
mones are secreted into tissue fluids and act locally on nearby
cells, as in the following examples:
Gastrointestinal mucosa produces hormones that are
important in the digestive process (eg, gastrin, entero-
gastrone, secretin, and cholecystokinin).
The kidneys produce erythropoietin, a hormone that
stimulates the bone marrow to produce red blood cells.
White blood cells produce cytokines that function as mes-
sengers among leukocytes in inflammatory and immune
processes.
Many body tissues produce prostaglandins and leuko-
trienes, which have a variety of physiologic effects.
Neoplasms also may produce hormones. In endocrine tis-
sues, neoplasms may be an added source of the hormone nor-
mally produced by the organ. In nonendocrine tissues, various
4. Discuss hormonal action at the cellular level.
5. Describe the second messenger roles of cyclic
adenosine monophosphate and calcium within
body cells.
6. Differentiate between physiologic and pharma-
cologic doses of hormonal drugs.
hormones may be produced. For example, lung tumors may
produce corticotropin (adrenocorticotropic hormone [ACTH]),
antidiuretic hormone, or parathyroid hormone; kidney tumors
may produce parathyroid hormone. The usual effects are those
of excess hormone secretion.
This chapter focuses on the traditional endocrine organs
and their hormones. Specific organs are discussed in the fol-
lowing chapters; general characteristics of the endocrine sys-
tem and hormones are described in the following sections and
in Box 221.
ENDOCRINE SYSTEM
NERVOUS SYSTEM INTERACTIONS
The endocrine and nervous systems are closely connected,
anatomically and physiologically, and work in harmony to in-
tegrate and regulate body functions. In general, the nervous
system regulates rapid muscular and sensory activities by se-
creting substances that act as neurotransmitters, circulating
hormones, and local hormones (eg, norepinephrine, epineph-
rine). The endocrine system regulates slow metabolic activities
by secreting hormones that control cellular metabolism, trans-
port of substances across cell membranes, and other functions
(eg, reproduction, growth and development, secretion).
The main connecting link between the nervous system and
the endocrine system is the hypothalamus, which responds to
nervous system stimulation by producing hormones. Thus,
secretion of almost all hormones from the pituitary gland is
controlled by the hypothalamus. Special nerve fibers origi-
nating in the hypothalamus and ending in the posterior pitu-
itary gland control secretions of the posterior pituitary. The
hypothalamus secretes hormones called releasing and in-
321
 322 SECTION 4 DRUGS AFFECTING THE ENDOCRINE SYSTEM
BOX 221
MAJOR HORMONES AND THEIR GENERAL FUNCTIONS
Anterior pituitary hormones are growth hormone (also called
somatotropin), corticotropin, thyroid-stimulating hormone, follicle-
stimulating hormone, luteinizing hormone, and prolactin. Most
of these hormones function by stimulating secretion of other
hormones.
Posterior pituitary hormones are antidiuretic hormone
(ADH or vasopressin) and oxytocin. ADH helps maintain fluid
balance; oxytocin stimulates uterine contractions during child-
birth.
Adrenal cortex hormones, commonly called corticosteroids,
include the glucocorticoids, such as cortisol, and the mineralocorti-
coids, such as aldosterone. Glucocorticoids influence carbohydrate
storage, exert anti-inflammatory effects, suppress corticotropin se-
cretion, and increase protein catabolism. Mineralocorticoids help
regulate electrolyte balance, mainly by promoting sodium retention
and potassium loss. The adrenal cortex also produces sex hormones.
The adrenal medulla hormones are epinephrine and norepinephrine
(see Chap. 17).
hibitory factors, which regulate functions of the anterior pi-
tuitary. The anterior pituitary, in turn, secretes hormones that
act on target tissues, usually to stimulate production of other
hormones. For example, hypothalamic corticotropin-releasing
hormone stimulates the anterior pituitary to produce corti-
cotropin, and corticotropin, in turn, stimulates the adrenal
cortex to produce cortisol. This complex interrelationship is
often referred to as the hypothalamicpituitaryadrenocortical
axis. It functions by a negative feedback system, in which
hormone secretion is stimulated when hormones are needed
and inhibited when they are not needed. The hypothalamic
pituitarythyroid axis also functions by a negative feedback
mechanism.
GENERAL CHARACTERISTICS
OF HORMONES
Hormones are extremely important in regulating body activ-
ities. Their normal secretion and function help to maintain the
internal environment and determine response and adaptation
to the external environment. Hormones participate in complex
interactions with other hormones and nonhormone chemical
substances in the body to influence every aspect of life.
Although hormones are usually studied individually, virtually
all endocrine functions are complex processes that are influ-
enced by more than one hormone.
Although hormones circulating in the bloodstream reach
essentially all body cells, some (eg, growth hormone, thyroid
hormone) affect almost all cells, whereas others affect spe-
cific target tissues (eg, corticotropin stimulates the adrenal
cortex). In addition, one hormone can affect different tissues
(eg, ovarian estrogen can act on ovarian follicles to promote
their maturation, on the endometrial lining of the uterus to
stimulate its growth and cyclic changes, on breast tissue to
stimulate growth of milk ducts, and on the hypothalamic
Thyroid hormones include triiodothyronine (T3 or liothyro-
nine) and tetraiodothyronine (T4 or thyroxine). These hormones
regulate the metabolic rate of the body and greatly influence
growth and development.
Parathyroid hormone, also called parathormone or PTH, reg-
ulates calcium and phosphate metabolism.
Pancreatic hormones are insulin and glucagon, which regu-
late the metabolism of glucose, lipids, and proteins.
Ovarian hormones (female sex hormones) are estrogens and
progesterone. Estrogens promote growth of specific body cells and
development of most female secondary sexual characteristics.
Progesterone helps prepare the uterus for pregnancy and the mam-
mary glands for lactation.
Testicular hormone (male sex hormone) is testosterone, which
regulates development of masculine characteristics.
Placental hormones are chorionic gonadotropin, estrogen,
progesterone, and human placental lactogen, all of which are con-
cerned with reproductive functions.
pituitary system to regulate its own secretion), or several hor-
mones can affect a single tissue or function (eg, catecholamines,
glucagon, secretin, and prolactin regulate lipolysis [release of
fatty acids from adipose tissue]).
Several hormones are secreted in cyclic patterns. For ex-
ample, ACTH, cortisol, and growth hormone are secreted in
24-hour (circadian) cycles, whereas estrogen and progestin
secretion is related to the 28-day menstrual cycle.
Hormone Pharmacokinetics
Protein-derived hormones (amines, amino acids, peptides,
and polypeptides) are synthesized, stored, and released into
the bloodstream in response to a stimulus. The steroid hor-
mones, which are synthesized in the adrenal cortex and go-
nads from cholesterol, are released as they are synthesized.
Most hormones are constantly present in the blood; plasma
concentrations vary according to body needs, the rate of syn-
thesis and release, and the rate of metabolism and excretion.
Protein-derived hormones usually circulate in an un-
bound, active form. Steroid and thyroid hormones are trans-
ported by specific carrier proteins synthesized in the liver.
(Some drugs may compete with a hormone for binding sites
on the carrier protein. If this occurs, hormone effects are en-
hanced because more unbound, active molecules are avail-
able to act on body cells.)
Hormones must be continuously inactivated to prevent
their accumulation and excessive effects. Several mecha-
nisms operate to eliminate hormones from the body. The
water-soluble, protein-derived hormones have a short dura-
tion of action and are inactivated by enzymes mainly in the
liver and kidneys. The lipid-soluble steroid and thyroid hor-
mones have a longer duration of action because they are
bound to plasma proteins. Once released by the plasma pro-
teins, these hormones are conjugated in the liver to inactive

forms and then excreted in bile or urine. A third, less com-
mon mechanism is inactivation by enzymes at receptor sites
on target cells.
Hormone Action at the Cellular Level
Hormones modify rather than initiate cellular reactions and
functions. Once hormone molecules reach a responsive cell,
they bind with receptors in the cell membrane (eg, cate-
cholamines and protein hormones) or inside the cell (eg, steroid
and thyroid hormones). The number of hormone receptors and
the affinity of the receptors for the hormone are the major
determinants of target cell response to hormone action.
The main target organs for a given hormone contain large
numbers of receptors. However, the number of receptors may
be altered by various conditions. For example, receptors may
be increased (called up-regulation) when there are low levels
of hormone. This allows the cell to obtain more of the needed
hormone than it can obtain with fewer receptors. Receptors
may be decreased (called down-regulation) when there are
excessive amounts of hormone. This mechanism protects the
cell by making it less responsive to excessive hormone lev-
els. Receptor up-regulation and down-regulation occur with
chronic exposure to abnormal levels of hormones. In addi-
tion, receptor proteins may be decreased by inadequate for-
mation or antibodies that destroy them. Thus, receptors are
constantly being synthesized and degraded, so the number of
receptors may change within hours. Receptor affinity for
binding with hormone molecules probably changes as well.
After binding occurs, the resulting hormonereceptor
complex initiates intracellular biochemical reactions, de-
pending on the particular hormone and the type of cell.
Many hormones act as a first messenger to the cell, and
the hormonereceptor complex activates a second mes-
senger. The second messenger then activates intracellular
structures to produce characteristic cellular functions and
products. Steroid hormones from the adrenal cortex, ovaries,
and testes stimulate target cells to synthesize various pro-
teins (eg, enzymes, transport and structural proteins) needed
for normal cellular function.
Second Messenger Systems
Three major second messenger systems, cyclic adenosine
monophosphate (cAMP), calciumcalmodulin, and phospho-
lipid products, are described in this section.
Cyclic AMP is the second messenger for many hormones,
including corticotropin, catecholamines, glucagon, thyroid-
stimulating hormone, follicle-stimulating hormone, luteinizing
hormone, parathyroid hormone, secretin, and antidiuretic hor-
mone. It is formed by the action of the enzyme adenyl cyclase
on adenosine triphosphate, a component of all cells and the
main source of energy for cellular metabolism. Once formed,
cAMP activates a series of enzyme reactions that alter cell
function. The amount of intracellular cAMP is increased
by hormones that activate adenyl cyclase (eg, the pituitary
CHAPTER 22 PHYSIOLOGY OF THE ENDOCRINE SYSTEM 323
hormones, calcitonin, glucagon, parathyroid hormone) and
decreased by hormones that inactivate adenyl cyclase
(eg, angiotensin, somatostatin). Cyclic AMP is inactivated
by phosphodiesterase enzymes.
Calcium is the second messenger for angiotensin II, a
strong vasoconstrictor that participates in control of arterial
blood pressure, and for gonadotropin-releasing hormone. The
postulated sequence of events is that hormone binding to re-
ceptors increases intracellular calcium. The calcium binds
with an intracellular regulatory protein called calmodulin.
The calciumcalmodulin complex activates protein kinases,
which then regulate contractile structures of the cell, cell mem-
brane permeability, and intracellular enzyme activity. Specific
effects include contraction of smooth muscle, changes in the
secretions produced by secreting cells, and changes in ciliary
action in the lungs.
Phospholipid products are mainly involved with local hor-
mones. Phospholipids are major components of the cell mem-
brane portion of all body cells. Some local hormones activate
cell membrane receptors and transform them into phospho-
lipase C, an enzyme that causes some of the phospholipids in
cell membranes to split into smaller molecules (eg, inositol
triphosphate and diacylglycerol). These products then act as
second messengers to intracellular structures. Inositol triphos-
phate mobilizes intracellular calcium ions and the calcium
ions then fulfill their functions as second messengers, as de-
scribed previously. Diacylglycerol activates an enzyme, pro-
tein kinase C, that is important in cell reproduction. Also, the
lipid component of diacylglycerol is arachidonic acid, the
precursor for prostaglandins, leukotrienes, and other local
hormones with extensive effects.
Steroid Stimulation of Protein Synthesis
Steroid hormones are lipid soluble and therefore cross cell
membranes easily. Once inside the cell cytoplasm, the hor-
mone molecules bind with specific receptor proteins. The
hormonereceptor complex then enters the nucleus of the cell
where it activates nucleic acids (DNA and RNA) and the
genetic code to synthesize new proteins.
Hormonal Disorders
Abnormal secretion and function of hormones, even minor
alterations, can impair physical and mental health. Malfunction
of an endocrine organ is usually associated with hyposecre-
tion, hypersecretion, or inappropriate secretion of its hor-
mones. Any malfunction can produce serious disease or death.
Hypofunction
Hypofunction may be associated with a variety of circum-
stances, including the following:
1. A congenital defect may result in the absence of an en-
docrine gland, the presence of an abnormally developed
 324 SECTION 4 DRUGS AFFECTING THE ENDOCRINE SYSTEM
gland, or the absence of an enzyme required for glandu-
lar synthesis of its specific hormone.
2. The endocrine gland may be damaged or destroyed by
impaired blood flow, infection or inflammation, auto-
immune disorders, or neoplasms.
3. The endocrine gland may atrophy and become less able
to produce its hormone because of aging, drug therapy,
disease, or unknown reasons.
4. The endocrine gland may produce adequate hormone,
but the hormone may not be able to function normally
because of receptor defects (not enough receptors or the
receptors present are unable to bind with the hormone).
5. Even if there is adequate hormone and adequate binding
to receptors, intracellular metabolic processes (eg, en-
zyme function, protein synthesis, energy production)
may not respond appropriately.
Hyperfunction
Hyperfunction is usually characterized by excessive hor-
mone production. Excessive amounts of hormone may occur
from excessive stimulation and enlargement of the endocrine
gland, from a hormone-producing tumor of the gland, or
from a hormone-producing tumor of nonendocrine tissues
(eg, some primary lung tumors produce antidiuretic hormone
and adrenocorticotropic hormone).
GENERAL CHARACTERISTICS
OF HORMONAL DRUGS
1. Hormones given for therapeutic purposes include nat-
ural hormones from human or animal sources and syn-
thetic hormones. Many of the most important hormones
have been synthesized, and these preparations may
have more potent and prolonged effects than the natu-
rally occurring hormones.
2. Hormones are given for physiologic or pharmacologic
effects. Physiologic use involves giving small doses as
a replacement or substitute for the amount secreted by
a normally functioning endocrine gland. Such use is in-
dicated only when a gland cannot secrete an adequate
amount of hormone. Examples of physiologic use in-
clude insulin administration in diabetes mellitus and
adrenal corticosteroid administration in Addisons dis-
ease. Pharmacologic use involves relatively large doses
for effects greater than physiologic effects. For exam-
ple, adrenal corticosteroids are widely used for anti-
inflammatory effects in endocrine and nonendocrine
disorders.
3. Hormones are powerful drugs that produce widespread
therapeutic and adverse effects.
4. Administration of one hormone may alter effects of
other hormones. These alterations result from the com-
plex interactions among hormones.
5. Hormonal drugs are more often given for disorders re-
sulting from endocrine gland hypofunction than for
those related to hyperfunction.
Review and Application Exercises
1. How do hormones function in maintaining homeostasis?
2. What is the connection between the nervous system and
the endocrine system?
3. What is meant by a negative feedback system?
4. Because classic hormones are secreted into blood and cir-
culated to essentially all body cells, why do they not affect
all body cells?
5. What are the functions and characteristics of the pituitary
gland?
SELECTED REFERENCES
Guyton, A. C. & Hall, J. E. (2000). Textbook of medical physiology, 10th ed.
Philadelphia: W. B. Saunders.
Matfin, G., Guven, S., & Kuenzi, J. A. (2002). Mechanisms of endocrine
control. In C. M. Porth (Ed.), Pathophysiology: Concepts of altered health
states, 6th ed., pp. 891902. Philadelphia: Lippincott Williams & Wilkins.