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Greenspans Basic & Clinical Endocrinology, 9e >

Chapter 4. Hypothalamus and Pituitary Gland

Bradley R. Javorsky, MD; David C. Aron, MD, MS; James W. Findling, MD; J. Blake Tyrrell, MD

Abbreviations
ACTHAdrenocorticotropic hormone
ADHAntidiuretic hormone (vasopressin)
CLIPCorticotropin-like intermediate lobe peptide
CRH Corticotropin-releasing hormone
CRHBP Corticotropin-releasing hormone-binding protein
FGF8 Fibroblast growth factor 8
FGFR1 Fibroblast growth factor receptor 1
FSH Follicle-stimulating hormone
GABA Gamma-aminobutyric acid
GHGrowth hormone (somatotropin)
GHBP Growth hormonebinding protein
GHRH Growth hormonereleasing hormone
GHS-R Growth hormone secretagogue receptor
GnRHGonadotropin-releasing hormone
hCG Human chorionic gonadotropin
hMGHuman menopausal gonadotropin
hPL Human placental lactogen
ICMA Immunochemiluminescent assay
IGF Insulin-like growth factor
IRMA Immunoradiometric assay
KAL1 Kallmann syndrome 1
LH Luteinizing hormone
-LPH -Lipotropin
Met-Enk Methionine-enkephalin
MEN Multiple endocrine neoplasia
MSH Melanocyte-stimulating hormone
Pit-1 Pituitary-specific positive transcription factor 1
POMC Pro-opiomelanocortin
PROK2 Prokineticin 2
PROKR2 Prokineticin receptor 2
Prop-1 Prophet of Pit-1
PRL Prolactin
PTTG Pituitary tumor transforming gene
SHBG Sex hormonebinding globulin
SIADH Syndrome of inappropriate secretion of antidiuretic hormone
TRH Thyrotropin-releasing hormone
TSH Thyroid-stimulating hormone (thyrotropin)
VIP Vasoactive intestinal peptide

Hypothalamus and Pituitary Gland: Introduction

The hypothalamus and pituitary gland form a unit that exerts control over the function of several endocrine glandsthyroid, adrenals,
and gonadsas well as a wide range of physiologic activities. This unit is highly conserved across vertebrate species and constitutes a
paradigm of neuroendocrinologybrainendocrine interactions. The actions and interactions of the endocrine and nervous systems,

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whereby the nervous system regulates the endocrine system and endocrine activity modulates the activity of the central nervous system,
constitute the major regulatory mechanisms for virtually all physiologic activities. These neuroendocrine interactions are also important
in pathogenesis. This chapter will review the normal functions of the pituitary gland, the neuroendocrine control mechanisms of the
hypothalamus, and the disorders of those mechanisms.
Nerve cells and endocrine cells, which are both involved in cell-to-cell communication, share certain characteristic featuressecretion
of chemical messengers (neurotransmitters or hormones) and electrical activity. A single chemical messengerpeptide or aminecan
be secreted by neurons as a neurotransmitter or neural hormone and by endocrine cells as a classic hormone. Examples of such
multifunctional chemical messengers are shown in Table 41. The cell-to-cell communication may occur by four mechanisms: (1)
autocrine communication via messengers that diffuse in the interstitial fluid and act on the cells that secreted them, (2) neural
communication via synaptic junctions, (3) paracrine communication via messengers that diffuse in the interstitial fluid to adjacent target
cells (without entering the bloodstream), and (4) endocrine communication via circulating hormones (Figure 41). The two major
mechanisms of neural regulation of endocrine function are direct innervation and neurosecretion (neural secretion of hormones). The
adrenal medulla, kidney, parathyroid gland, and pancreatic islets are endocrine tissues that receive direct autonomic innervation (see
Chapters 9, 10, 11). An example of neurosecretory regulation is the hormonal secretion of certain hypothalamic nuclei into the portal
hypophysial vessels, which regulate the hormone-secreting cells of the anterior lobe of the pituitary. Another example of neurosecretory
regulation is the posterior lobe of the pituitary gland, which is made up of the endings of neurons whose cell bodies reside in
hypothalamic nuclei. These neurons secrete vasopressin and oxytocin into the general circulation.
Table 41 Neuroendocrine Messengers: Substances that Function as Neurotransmitters, Neural Hormones, and Classic Hormones.
Neurotransmitter (Present in Nerve Hormone Secreted by
Hormone Secreted by
Endings)
Neurons
Endocrine Cells
Dopamine
+
+
+
Norepinephrine
+
+
+
Epinephrine
+
+
Somatostatin
+
+
+
Gonadotropin-releasing hormone
+
+
+
(GnRH)
Thyrotropin-releasing hormone
+
+
(TRH)
Oxytocin
+
+
+
Vasopressin
+
+
+
Vasoactive intestinal peptide
+
+
Cholecystokinin (CCK)
+
+
Glucagon
+
+
Enkephalins
+
+
Pro-opiomelanocortin derivatives +
+
Other anterior pituitary hormones +
+
Figure 41

Intercellular communication by chemical mediators.

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Anatomy and Embryology

The anatomic relationships between the pituitary and the main nuclei of the hypothalamus are shown in Figure 42. The posterior lobe
of the pituitary (neurohypophysis) is of neural origin, arising embryologically as an evagination of the ventral hypothalamus and the
third ventricle. The neurohypophysis consists of the axons and nerve endings of neurons whose cell bodies reside in the supraoptic and
paraventricular nuclei of the hypothalamus and supporting tissues. This hypothalamic-neurohypophysial nerve tract contains
approximately 100,000 nerve fibers. Repeated swellings along the nerve fibers ranging in thickness from 1 to 50 m constitute the
nerve terminals.
Figure 42

The human hypothalamus, with a superimposed diagrammatic representation of the portal hypophysial vessels.
(Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 15th ed. McGraw-Hill; 1993).
The human fetal anterior pituitary anlage is initially recognizable at 4 to 5 weeks of gestation, and rapid cytologic differentiation leads
to a mature hypothalamic-pituitary unit at 20 weeks. The anterior pituitary (adenohypophysis) originates from Rathke pouch, an
ectodermal evagination of the oropharynx, and migrates to join the neurohypophysis. The portion of Rathke pouch in contact with the
neurohypophysis develops less extensively and forms the intermediate lobe. This lobe remains intact in some species, but in humans its
cells become interspersed with those of the anterior lobe and develop the capacity to synthesize and secrete pro-opiomelanocortin
(POMC) and adrenocorticotropic hormone (ACTH). Remnants of Rathke pouch may persist at the boundary of the neurohypophysis,
resulting in small colloid cysts. In addition, cells may persist in the lower portion of Rathke pouch beneath the sphenoid bone, the
pharyngeal pituitary. These cells have the potential to secrete hormones and have been reported to undergo adenomatous change.
The pituitary gland itself lies at the base of the skull in a portion of the sphenoid bone called the sella turcica (Turkish saddle). The
anterior portion, the tuberculum sellae, is flanked by posterior projections of the sphenoid wings, the anterior clinoid processes. The
dorsum sellae forms the posterior wall, and its upper corners project into the posterior clinoid processes. The gland is surrounded by
dura, and the roof is formed by a reflection of the dura attached to the clinoid processes, the diaphragma sellae. The arachnoid
membrane and, therefore, cerebrospinal fluid are prevented from entering the sella turcica by the diaphragma sellae. The pituitary stalk
and its blood vessels pass through an opening in this diaphragm. The lateral walls of the gland are in direct apposition to the cavernous

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sinuses and separated from them by dural membranes. The optic chiasm lies 5 to 10 mm above the diaphragma sellae and anterior to
the stalk (Figure 43).
Figure 43

Anatomic relationships and blood supply of the pituitary gland.

(Reproduced, with permission, from Frohman LA. Diseases of the anterior pituitary. In: Felig P, Baxter JD, Frohman LA, eds.
Endocrinology and Metabolism. 3rd ed. McGraw-Hill; 1995).
The size of the pituitary gland, of which the anterior lobe constitutes two-thirds, varies considerably. It measures approximately 15 10
6 mm and weighs 500 to 900 mg; it may double in size during pregnancy. The sella turcica tends to conform to the shape and size of
the gland, and for that reason there is considerable variability in its contour.

Blood Supply
The anterior pituitary is the most richly vascularized of all mammalian tissues, receiving 0.8 mL/g/min from a portal circulation
connecting the median eminence of the hypothalamus and the anterior pituitary. Arterial blood is supplied from the internal carotid
arteries via the superior, middle, and inferior hypophysial arteries. The superior hypophysial arteries form a capillary network in the
median eminence of the hypothalamus that recombines in long portal veins draining down the pituitary stalk to the anterior lobe, where
they break up into another capillary network and re-form into venous channels. The pituitary stalk and the posterior pituitary are
supplied directly from branches of the middle and inferior hypophysial arteries (see Figures 42 and 43).
Venous drainage of the pituitary, the route through which anterior pituitary hormones reach the systemic circulation, is variable, but
venous channels eventually drain via the cavernous sinus posteriorly into the superior and inferior petrosal sinuses to the jugular bulb
and vein (Figure 44). The axons of the neurohypophysis terminate on capillaries that drain via the posterior lobe veins and the
cavernous sinuses to the general circulation. The hypophysial portal system of capillaries allows control of anterior pituitary function
by the hypothalamic hypophysiotropic hormones secreted into the portal hypophysial vessels. This provides a short, direct connection
to the anterior pituitary from the ventral hypothalamus and the median eminence (Figure 45). There may also be retrograde blood flow
between the pituitary and hypothalamus, providing a possible means of direct feedback between pituitary hormones and their
neuroendocrine control centers.
Figure 44

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Venous drainage of the pituitary glandthe route by which adenohypophysial hormones reach the systemic circulation.
(Reproduced, with permission, from Findling JW, et al. Selective venous sampling for ACTH in Cushing's syndrome: differentiation
between Cushing's disease and the ectopic ACTH syndrome. Ann Intern Med. 1981;94:647).
Figure 45

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Secretion of hypothalamic hormones. The hormones of the posterior lobe (PL) are released into the general circulation from the
endings of supraoptic and paraventricular neurons, whereas hypophysiotropic hormones are secreted into the portal hypophysial
circulation from the endings of arcuate and other hypothalamic neurons (AL, anterior lobe; ARC, arcuate and other nuclei; MB,
mamillary bodies; OC, optic chiasm; PV, paraventricular nucleus; SO, supraoptic nucleus).

Pituitary Development and Histology

Anterior pituitary cells were originally classified as acidophils, basophils, and chromophobe cells based on staining with hematoxylin
and eosin. Immunocytochemical and electron microscopic techniques now permit classification of cells by their specific secretory
products: somatotrophs (growth hormone [GH]-secreting cells), lactotrophs (prolactin [PRL]-secreting cells), thyrotrophs (cells
secreting thyroid-stimulating hormone [thyrotropin; TSH]), corticotrophs (cells-secreting ACTH [corticotropin] and related peptides),
and gonadotrophs (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]secreting cells). The development of the
pituitary gland and the emergence of the distinct cell types from common primordial cells are controlled by a limited set of
transcription factors, most notably Prop1 and Pit1 (Figure 46). The individual hormone-secreting cells emerge in a specific order and
from distinct lineages. Abnormalities of pituitary and lineagespecific transcription factors have been associated with the development
of hypopituitarism. Although traditionally the pituitary has been conceptualized as a gland with distinct and highly specialized cells
that respond to specific hypothalamic and peripheral hormones, it has become clear that local (ie, paracrine) factors also play a role in
normal pituitary physiology.
Figure 46

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