Download Introduction To Endocrinology: The Hypothalamic

Introduction To Endocrinology:
The Hypothalamic-Pituitary Axis
Keith L. Parker
and Bernard P. Schimmer
ENDOCRINOLOGY AND HORMONES:
GENERAL CONCEPTS
Endocrinology analyzes the biosynthesis of hormones,
their sites of production, and the sites and mechanisms
of their action and interaction. The term hormone is of
Greek origin and classically refers to chemical messengers that circulate in body fluids and produce specific
effects on cells distant from their point of origin. The
major functions of hormones include the regulation of
energy storage, production, and utilization; the adaptation to new environments or conditions of stress; the
facilitation of growth and development; and the maturation and function of the reproductive system. Although
hormones were originally defined as products of ductless glands, we now appreciate that many organs that
were not classically considered as “endocrine” (e.g., the
heart, kidneys, GI tract, adipocytes, and brain) synthesize and secrete hormones that play key physiological
roles; many of these hormones are now employed either
diagnostically or therapeutically in clinical medicine. In
addition, the field of endocrinology has expanded to
include the actions of growth factors acting by means of
autocrine and paracrine mechanisms, the influence of
neurons—particularly those in the hypothalamus—that
regulate endocrine function, and the reciprocal interactions of cytokines and other components of the immune
system with the endocrine system.
As discussed in Chapter 3, hormones generally
exert their actions on target cells via a plenitude of
receptors, including heptaspanning GPCRs, monospanning membrane tyrosine kinases and guanylyl cyclases,
cytokine receptors, ligand-activated ion channels, and
nuclear transcription factors. Conceptually, it is useful to
divide hormones into two classes: those that act predominantly via nuclear receptors to modulate transcription in target cells and those that typically act via
membrane receptors to exert rapid effects on signal
transduction pathways. Steroid hormones, thyroid hormone, and vitamin D belong to the first class, whereas
peptide and amino acid hormones are generally
assigned to the second class. The receptors for both
classes of hormones provide tractable targets for a
diverse group of compounds that are among the most
widely used drugs in clinical medicine.
DISORDERS OF ENDOCRINE
REGULATION
Because of their potent effects, circulating levels of hormones generally are tightly regulated within a normal
range. The physiological strategies used to maintain the
appropriate levels of hormones range from relatively
simple ones involving direct feedback or feed-forward
mechanisms (e.g., the secretion of parathyroid hormone by the parathyroid glands is inversely related to
the serum Ca2+ concentration, which is sensed by a
GPCR termed the Ca2+-sensing receptor; Chapter 44)
to more complex ones involving reciprocal interactions
among the hypothalamus, anterior pituitary, and
endocrine glands (see the section “The HypothalamicPituitary-Endocrine Axis”).
Regardless of the mechanism, normal regulation
can be perturbed in disease states when a given hormone
is either over or underproduced or when its signaling
mechanisms are impaired. Understanding the normal
regulation and actions of the various hormones is critical to both diagnosis and treatment of these endocrine
disorders. Chapters 38 through 44 describe the different
endocrine organs and the drugs that are employed to
affect their function or to mimic or block their hormonal
products.
THE HYPOTHALAMICPITUITARY-ENDOCRINE AXIS
Many of the classic endocrine hormones (e.g., cortisol,
thyroid hormone, sex steroids, growth hormone) are
regulated by complex reciprocal interactions among the
hypothalamus, anterior pituitary, and endocrine glands
(Table 38–1). These interactions permit precise control
over the levels of circulating hormones and also provide a means to alter hormone levels under special
physiological or pathological circumstances.
The basic organization of the hypothalamicpituitary-endocrine axis is summarized in Figure 38–1.
Discrete sets of hypothalamic neurons produce different releasing hormones, which are axonally transported
to the median eminence. Upon stimulation, these neurons secrete their respective hypothalamic releasing hormones into the hypothalamic-adenohypophyseal plexus,
which flows to the anterior pituitary gland. The hypothalamic releasing hormones bind to membrane receptors on specific subsets of pituitary cells and stimulate
the secretion of the corresponding pituitary hormones.
The pituitary hormones, which can be thought of as the
master signals, then circulate to the target endocrine
glands, where they again activate specific receptors to
stimulate the synthesis and secretion of the target
endocrine hormones. These interactions thus represent
feed-forward regulation in which the master (signal)
hormones stimulate the production of target hormones
by the endocrine organs.
Superimposed on this positive feed-forward regulation is negative feedback regulation, which permits
precise control of hormone levels. Figures 38–2 and
38–7 show examples of this negative feedback regulation. Typically, the endocrine target hormone circulates
to both the hypothalamus and pituitary, where it acts
via specific receptors to inhibit the production and
secretion of both its hypothalamic releasing hormone
and the regulatory pituitary hormone, thereby tightly
regulating target hormone levels. In addition, other
brain regions have inputs to the hypothalamic releasing
neurons, further integrating the regulation of hormone
levels in response to diverse stimuli.
An understanding of this regulation facilitates the
diagnosis and management of a number of endocrine
diseases. Endocrine deficiency states can be divided
into those with impaired function at the level of the target endocrine gland (primary disease; as is the case in
the autoimmune destruction of the adrenal or thyroid
glands) and those with defects at the level of the pituitary gland and/or hypothalamus that impair delivery of
the pituitary trophic hormone to its target gland
(secondary/tertiary disease). In primary hypofunction,
the production of the target endocrine hormone will be
impaired; however, the hypothalamus and pituitary will
sense the diminished feedback inhibition and the anterior pituitary gland will secrete higher than normal
levels of the signal hormone. In secondary hypofunction,
both the signal hormone and the target hormone will be
below the normal range.
Table 38–1
Hormones that Integrate the Hypothalamic-Pituitary-Endocrine Axis
HYPOTHALAMIC RELEASING HORMONE
PITUITARY TROPHIC (SIGNAL) HORMONE
TARGET HORMONE(S)
Growth hormone-releasing hormone
(GHRH)
Somatostatin (SST)a
Dopamine (DA)b
Corticotropin-releasing hormone (CRH)
Thyrotropin-releasing hormone (TRH)
Gonadotropin-releasing hormone (GnRH)
Growth hormone (GH)
IGF-1
a
Growth hormone
Prolactin
Corticotropin
Thyroid-stimulating hormone (TSH)
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Somatostatin inhibits growth hormone release.
Dopamine inhibits prolactin release.
IGF-1, insulin-like growth factor-1; DHEA, dehydroepiandrosterone; f, female; m, male.
b
—
Cortisol/DHEA
Thyroid hormone
Estrogen
Progesterone/Estrogen (f)
Testosterone (m)
PVN
(TRH, CRH, SST)
SON, PVN
(AVP, OXY)
Hypothalamus
ARC
(GHRH, GnRH,
DA)
Posterior
lobe
Releasing
factors
Portal
system
AVP,
OXY
Trophic hormones
(ACTH, TSH, GH,
LH, FSH, prolactin)
Kidney, uterus,
mammary gland
Figure 38–1. Organization of the anterior and posterior pituitary
gland. Hypothalamic neurons in the supraoptic (SON) and paraventricular (PVN) nuclei synthesize arginine vasopressin (AVP)
or oxytocin (OXY). Most of their axons project directly to the
posterior pituitary, from which AVP and OXY are secreted into
the systemic circulation to regulate their target tissues. Neurons
that regulate the anterior lobe cluster in the mediobasal hypothalamus, including the PVH and the arcuate (ARC) nuclei. They
secrete hypothalamic releasing hormones, which reach the anterior pituitary via the hypothalamic-adenohypophyseal portal system and stimulate distinct populations of pituitary cells. These
cells, in turn, secrete the trophic (signal) hormones, which regulate endocrine organs and other tissues. See Table 38-1 for
abbreviations.
Hormone excess similarly can result either from
primary disorders at the level of the target endocrine
glands (e.g., a hyperfunctioning tumor of the adrenal cortex that oversecretes cortisol) or from secondary disorders at the level of the pituitary gland (e.g., a pituitary
corticotrope adenoma that oversecretes corticotropin, the
predominant stimulator of adrenal glucocorticoid biosynthesis). Again, knowledge of the levels of the pituitary
signal hormone and the target hormone allows the clinician to identify the site of the endocrine disorder.
The peptide hormones of the anterior pituitary are essential for the regulation of growth and development, reproduction, response to stress, and intermediary
metabolism. Their synthesis and secretion are controlled
by hypothalamic hormones and by hormones from the
peripheral endocrine organs. A large number of disease
states, as well as a diverse group of drugs, also affect
their secretion. The complex interactions among the
hypothalamus, pituitary, and target endocrine glands
provide elegant examples of the integrated feedback regulation described earlier. Clinically, an improved understanding of the mechanisms that underlie these
interactions provides the rationale for diagnosing and
treating endocrine disorders and for predicting certain
side effects of drugs that affect the endocrine system.
Moreover, the elucidation of the structures of the anterior pituitary hormones and hypothalamic releasing hormones and advances in protein chemistry and molecular
biology have made it possible to produce synthetic peptide agonists and antagonists that have important diagnostic and therapeutic applications.
The anterior pituitary hormones can be classified
into three different groups based on their structural features (Table 38–2). Corticotropin (adrenocorticotrophic
hormone, ACTH) and α-melanocyte-stimulating hormone (α-MSH) are part of a family of peptides derived
from pro-opiomelanocortin (POMC) by proteolytic
processing (Chapters 18 and 42). Growth hormone
(GH) and prolactin belong to the somatotropic family
of hormones, which in humans also includes placental
lactogen. The glycoprotein hormones—thyroidstimulating hormone (TSH; also called thyrotropin),
luteinizing hormone (LH; also called lutropin), and folliclestimulating hormone (FSH; also called follitropin)—
share a common α-subunit but have different β-subunits
that determine their distinct biological activities. In
humans, the glycoprotein hormone family also includes
human chorionic gonadotropin (hCG).
The synthesis and release of anterior pituitary
hormones are influenced by the central nervous system
(CNS). Their secretion is positively regulated by a
group of peptides referred to as hypothalamic releasing hormones, which are released from hypothalamic neurons in the region of the median eminence and
reach the anterior pituitary through the hypothalamicadenohypophyseal portal system (Figure 38–1). The
hypothalamic- releasing hormones include corticotropinreleasing hormone (CRH), growth hormone–releasing
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CHAPTER 38 INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS
Anterior
lobe
PITUITARY HORMONES AND THEIR
HYPOTHALAMIC RELEASING FACTORS
Table 38–2
Properties of the Protein Hormones of the Human Adenohypophysis and Placenta
HORMONE
MASS
(daltons)
PEPTIDE
CHAINS
AMINO ACID
RESIDUES
CHROMOSOMAL
LOCATION
Somatotropic hormones
Growth hormone (GH)
Prolactin (PRL)
Placental lactogen (PL)
22,000
23,000
22,125
1
1
1
191
199
190
17q22-24
6p22.2-21.3
17q22-24
Glycoprotein hormones
Luteinizing hormone (LH)
29,400
2
32,600
2
38,600
2
2
6q12.q21
19q13.3
6q12.q21
11p13
6q12.q21
19q13.3
6q12.q21
1p13
Heterodimeric glycoproteins with a common
α-subunit and unique
β-subunits that determine biological
specificity
28,000
α-92
β-121
α-92
β-111
α-92
β-145
α-92
β-118
4500
1650
1
1
39
13
2p22.3
These peptides are derived
by proteolytic hormone
processing of the
common precursor,
pro-opiomelanocortin
(POMC)
Follicle-stimulating
hormone (FSH)
Human chorionic
gonadotropin (hCG)
Thyroid-stimulating
hormone (TSH)
POMC-derived hormones*
Corticotropin (ACTH)
α-Melanocyte-stimulating
(α-MSH)
COMMENTS
*See Chapter 42 for further discussion of POMC-derived peptides, including ACTH and α-MSH.
hormone (GHRH), gonadotropin-releasing hormone
(GnRH), and thyrotropin-releasing hormone (TRH).
Somatostatin (SST), another hypothalamic peptide,
negatively regulates secretion of pituitary GH and TSH.
The neurotransmitter dopamine inhibits the secretion
of prolactin by lactotropes.
The posterior pituitary gland, also known as the
neurohypophysis, contains the endings of nerve axons
arising from distinct populations of neurons in the
supraoptic and paraventicular nuclei of the hypothalamus that synthesize either arginine vasopressin or
oxytocin (Figure 38–1). Arginine vasopressin plays an
important role in water homeostasis (Chapter 25);
oxytocin plays important roles in labor and parturition
and in milk letdown, as discussed in the following
sections and in Chapter 66.
biological features, thus providing a rationale for discussing them together. The somatotropes and lactotropes, the pituitary cells that produce GH and
prolactin, respectively, derive during pituitary development from a common precursor and are eosinophilic in
histological sections. Consistent with their common origin, defects in certain transcription factors affect both
cell lineages. In addition to their structural similarities,
GH and prolactin act via membrane receptors that
belong to the cytokine receptor family and modulate
target cell function via very similar signal transduction
pathways (Chapter 3). The secretion of both hormones
is subject to strong inhibitory input from hypothalamic
neurons; for prolactin, this negative dopaminergic input
clearly is the predominant regulator of secretion.
Finally, several drugs that are used to treat excessive
secretion of these hormones are effective to varying
degrees for both GH and prolactin.
SOMATOTROPIC HORMONES: GROWTH
HORMONE AND PROLACTIN
Physiology of the Somatotropic Hormones
GH and prolactin are structurally related members of
the somatotropic hormone family and share many
Structures of the Somatotropic Hormones. The gene
encoding human GH resides on the long arm of