C h a p t e r 3 1
Mechanisms of Endocrine Control
759
the cell membrane. The influx of ions then serves as an
intracellular signal to convey the hormone’s message to
the interior of the cell. In many instances, the activation
of hormone receptors results in the opening of calcium
channels, with the increasing intracellular concentration
of calcium ions acting as the signal that elicits the cel-
lular response.
Nuclear Receptors.
A second type of receptor mecha-
nism is involved in mediating the action of thyroid and
steroid hormones, as well as vitamin D, retinoic acid,
and other molecules. In contrast to peptide and cate-
cholamine hormones, these hormones enter the cell and
bind to receptors in the cell nucleus that are gene regula-
tory proteins. Many of these hormones and molecules
bind to receptors in the cytoplasm, and the hormone–
receptor complexes then travel to the nucleus. Nuclear
receptors can also be activated by second messenger sig-
naling pathways, thereby linking cell surface receptors
to nuclear receptor activation pathways.
Several subfamilies of nuclear receptors are currently
recognized on the basis of structural similarity. One
subfamily consists of receptors for thyroid hormone
and vitamin D. A second subfamily consists of gluco-
corticoid, progesterone, androgen, and estrogen recep-
tors. Other subfamilies contain “orphan receptors” for
which natural ligands have not as yet been identified.
Activated nuclear receptors act by binding to deoxy-
ribonucleic acid (DNA) response elements in the pro-
moter sites where gene transcription is initiated. These
DNA-binding elements, which are termed
hormone
response elements
, then activate or suppress intracellular
mechanisms such as gene activity, with the subsequent
production or inhibition of mRNA and protein synthe-
sis. The importance of the nuclear effects of thyroid and
steroid hormones is illustrated by the fact that each reg-
ulates protein synthesis. Proteins whose synthesis is reg-
ulated up or down by these hormones may be enzymes,
structural proteins, receptor proteins, or transcriptional
proteins that regulate the expression of other genes, or
proteins that are exported from the cell.
Some nuclear receptors are regulated by intracellular
metabolites rather than secreted signal molecules. The
peroxisome proliferator-activated receptors (PPARs),
for example, bind intracellular lipid metabolites and
regulate the transcription of genes involved in lipid
metabolism and adipose tissue metabolism. The thiazoli-
dinedione medications, which are used in the treatment
of type 2 diabetes mellitus, act at the level of nuclear
PPAR-
γ
receptors to promote glucose uptake and utili-
zation by adipose tissue cells (see Chapter 33).
Regulation of Hormone Levels
Hormone secretion varies widely over a 24-hour period.
Some hormones, such as growth hormone (GH) and adre-
nocorticotropic hormone (ACTH), have diurnal fluctua-
tions that vary with the sleep–wake cycle. Others, such
as the female sex hormones, are secreted in a complicated
cyclic manner. The levels of hormones such as insulin and
antidiuretic hormone (ADH) are regulated by feedback
mechanisms that monitor substances such as glucose
(insulin) and water (ADH) in the body. The levels of many
of the hormones are regulated by feedback mechanisms
that involve the hypothalamic-pituitary–target cell system.
Hypothalamic-Pituitary Regulation
The hypothalamus and pituitary gland, also known as
the
hypophysis
, form a unit that exerts control over
many functions of several endocrine glands as well as
a wide range of other physiologic functions. These two
structures are connected by blood flow in the hypophy-
sial portal system, which begins in the hypothalamus
and drains into the anterior pituitary gland, and by the
nerve axons that connect the supraoptic and paraven-
tricular nuclei of the hypothalamus with the posterior
pituitary gland (Fig. 31-4).
Hypothalamic Hormones.
The synthesis and release
of anterior pituitary hormones are largely regulated by
the action of releasing or inhibiting hormones from the
hypothalamus, which is the coordinating center of the
brain for endocrine, behavioral, and autonomic nervous
system function. It is at the level of the hypothalamus that
emotion, pain, body temperature, and other neural input
are communicated to the endocrine system. The poste-
rior pituitary hormones, ADH and oxytocin, are synthe-
sized in the cell bodies of neurons in the hypothalamus
that have axons that travel to the posterior pituitary.
The hypothalamic hormones that regulate the secre-
tion of anterior pituitary hormones include GH-releasing
hormone (GHRH), somatostatin, dopamine, TRH, cor-
ticotropin-releasing hormone (CRH), and gonadotro-
pin-releasing hormone (GnRH). With the exception of
GH and prolactin, most of the pituitary hormones are
regulated by hypothalamic stimulatory hormones. GH
secretion is stimulated by GHRH; thyroid-stimulating
hormone (TSH) by TRH; adrenocorticotropic hormone
(ACTH) by CRH; and luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) by GnRH. The
secretion of prolactin, which is also produced by cells
in the anterior pituitary gland, is inhibited by dopamine
from the hypothalamus. Drugs that interfere with the
synthesis or action of dopamine, such as some of the
antipsychotic medications, increase prolactin secretion.
The activity of the hypothalamus is regulated by
both hormonally mediated signals (e.g., negative feed-
back signals) and by neuronal input from a number of
sources. Neuronal signals are mediated by neurotrans-
mitters such as acetylcholine, dopamine, norepineph-
rine, serotonin,
γ
-aminobutyric acid (GABA), and
opioids. Cytokines that are involved in immune and
inflammatory responses, such as the interleukins, also
are involved in the regulation of hypothalamic function
(see Chapter 15). This is particularly true of the hor-
mones involved in the hypothalamic-pituitary-adrenal
axis. Thus, the hypothalamus can be viewed as a bridge
by which signals from multiple systems are relayed to
the pituitary gland.
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