Ebook BRS Cell biology and histology (7th edition): Part 2

Endo crine System

I. OVERVIEW-THE ENDOCRINE SYSTEM
A. The endocrine system is composed of several ductless glands, cl usters of cells within certain
organs, and isolated single endocrine cel ls, known as the diffuse neuroendocrine system (DNES)
cells, located in the epithelial lining of the respiratory and gastrointestinal systems (discussed in
chapters 15 and 1 6, respectively) .
B. Glands of the endocrine system include the pituitary gland (and a region of the brain known as
the hypothalamus), as well as the thyro id, parathyroid, adrenal, and pineal glands. Additional
components of the endocrine system, such as the Islets of Langerhans, adipose tissue, female
gonads, and male gonads, are discussed in the pertinent chapters.
C. Function. The endocrine system secretes hormones into nearby capillaries and interacts with the
nervous system to modulate and control the body's metabolic activities.

Hormones are chemical messengers that are carried via the bloodstream to distant target cells. They
include low-molecular-weight water-so luble proteins, polypeptides, and amino acids (e.g., insulin,
glucagon, follicle-stimulating hormone [FSH]) and l i pid-soluble substances, principally the steroid
hormones (e.g., progesterone, estradiol, and testosterone).
A. Water-soluble hormones interact with specific cell surface receptors on target cells, which
communicate a message that generates a biological response by the cell.
1. G protein-li nked receptors are used by some hormones (e.g., epinephrine, thyroid-stimulating
hormone [TSH], serotonin). Binding of the hormone to the G protein-linked receptor leads to
the production of a second messenger that evokes a target-cell response.
2. Catalytic receptors are used by insulin and growth hormone. Binding of the hormone to the
catalytic receptor activates protein kinases that phosphorylate target proteins.
B. Lipid-soluble hormones diffuse across the plasma membrane of target cells and bind to specific
receptors in the cytosol or in the nucleus, forming hormone-receptor complexes that regulate
transcription of deoxyribonucleic acid (DNA) .

221

222

BRS Cell B iology and H istology

The pituitary gland lies below the hypothalamus in a bony housing known as the hypophyseal fossa,
a depression in the se lla turcica of the sphenoid bone located in the base of the middle cranial fossa
of the skull.
The hypothalamus is a region of the diencephalon of the brain; it possesses nuclei that are struc­
turally and functionally linked to the pituitary gland. The structural link is via a series of axons whose
cell bodies are located in the supraoptic and paraventricular nuclei of the hypothalamus. These axons
form the hypothalamo-hypophysea l tract and terminate in the pars nervosa of the pituitary gland,
where they store and, when needed, release their hormones. The functional connection is via releas­
ing hormones that are synthesized in the arcuate, pa raventri cular (and medial paraventricular), peri­
ventricular, ventromedial, and dorsal nuclei of the hypothalamus. These hormones are released by
the neurons located in these nuclei, enter a capillary bed, and make their way, via the hypophyseal
porta l system t o a second capillary b e d i n the anterior lobe of the pituitary gland, leave the capillary
bed, and bind to their respective target cells in the anterior pituitary.
The pituitary gland is a relatively small gland, weighing only about 0.6 g in men and 1 . 2 g in
women who are pregnant or who have given birth to two or more children. The pituitary is divided
into two major subdivisions, the adenohypophysis and the neurohypophysis (Figure 1 3 . 1 ) . Each sub­
division is derived from a distinct embryonic analog, which is reflected in its unique cellular constitu­
ents and functions.
A. The adenohypophysis is also called the anterior pituitary gland (Figures 1 3 . 1 and 13.2). It originates
from an ectodermal diverticulum of the stomodeum (Rathke pouch). The adenohypophysis is
subdivided into the pars d ista l is, pars i ntermedia, and pars tuberalis.

1. The pars distalis is supported by a connective tissue capsule and framework. It consists of
irregular cords composed of two types of parenchymal cells, chromoph ils and chromophobes,
lying adjacent to fenestrated capillaries.

a . Chromophils (Figures 1 3 . 1 and 13.3)
(1 ) Overview. Chromophils are parenchymal cells that stain intensely because of their
hormone-containing secretory granules. They synthesize, store, and release several
hormones. They are regulated by specific stimulatory and inhibitory hormones produced
by neurons, referred to as neurosecretory cel ls, in the hypothalamus. These hormones
are conveyed to the pars distalis via a system of portal blood vessels originating in the

median eminence.
(2) Types. Chromophils are classified into two types, acidophils and basophils, depending
on the dyes they bind using special histological stains. With hematoxylin-eosin stain,
the distinction between the two cell types is much less obvious.
(a) Acidophils (Tables 1 3 . 1 and 13.2) bind acidic dyes and often stain orange or red.
They are small cells of two subtypes: somatotrophs and mammotrophs.
1 . Somatotrophs constitute about 50% of the chromophils and produce
somatotropin (g rowth hormone). They are stimulated by somatotropi n-releasing
hormone and are inhibited by somatostatin.
2. Mammotrophs (lactotrophs) constitute about 10% of the chromophil population,
except in multiparous women, where they may be as high as 30%. Mammotrophs
produce prolactin, which is stored in small secretory granules. They are
stimulated by prolacti n-releasing hormone and thyrotropi n-releasing hormone
(TRH ) and are inhibited by dopamine (until re-identified that it was designated as

prolacti n-inhibiting hormone).
(b) Basophils (Tables 13.1 and 13.2) bind basic dyes and typically stain blue. They
include three subtypes: corticotrophs, thyrotrophs, and gonadotrophs.

1 . Corticotrophs constitute about 10% of the chromophil population. They produce
pro-opiomela nocortin (POMC) whose by-products are adrenocorticotropic
hormone (ACTH), melanocyte-stimulating hormone (MSH), and lipotropic

l!iitJ'!1tilU Endocrine System
Neu rosecretory c e l l s

Parave ntricular
nuclei

located i n hypothalamus
secrete releas i n g and
i n h i bitory hnnmnr''"'

�

Hyperglyce m i a

223

Hypothalamus

M uscle

Elevation

, /
JC

Adipose
tissue

of free

Mammary

fatty acids

gland

·

� Ovu l at i o n :

p rogestero n e

secretion

Milk
secretion

F I G U R E 13.1 . An i l l u stratio n of the p itu ita ry g l a n d , s h owing its c o n n ecti o n s with the hypoth a l a m u s, the h o r m o n e s

it r e l e a ses, a n d th e effe cts of th e s e h o r m o n e s o n o r g a n s a n d tis s u e s of the b o dy. A D H , a ntid i u reti c h o rm o n e ; ACTH,
a d re n o c o rtic otro p i c h o r m o n e ; TS H , thyro i d -sti m u lati n g h o r m o n e ; FS H , fo l l i c l e -sti m u lating h o r m o n e ; LH, l ute i n iz i n g
h o r m o n e . I From Gartner LP. H iatt JL. Color Atlas o f Histology. 5th ed. Baltimore. M D : Lippincott William & Wilkins; 2009:206.)

hormone (LTH ), a precursor of�-endorphin. They are stimulated by corticotropin­
releasing hormone.
2. Thyrotrophs constitute about 5% of the chromophil population, produce TSH,
and are stimulated by TRH .

224

BRS Cell B iology and H istology
Source of hypophysiotropic
hormones (releasing
factors) --------,.

Source of ADH and oxytocin

-�·�� Wit.li?..----�--'<-T-- Primary capillary

plexus

Superior hypophyseal
artery
a------ Artery of trabecula
....,.k-..
--- Long portal veins

Posterior pituitary
(neurohypophysis)

Anterior pitu itary
(adenohypophysis)

Hormones stored
at fiber linings ---4-...._�
_ -•n•
GH
TSH

ACTH
FSH
LH
LTH
MSH
I nferior hypophyseal artery
F I G U R E 1 3.2. A d i a g ra m of the pitu ita ry g l a n d s h owing its c o n n e ctions to the hypoth a l a m u s, sites of h o r m o n e synth esis a n d

sto rage, a n d v a s c u l a rizati o n . The a d e n ohypop hysis i s s h own at the right a n d c o n sists of the p a rs d ista l is, p a rs tu b e r a l is,
and p a rs i nte r m e d i a ( n ot s h own). The n e u rohypop hysis c o n s ists of the infu n d i b u l u m (sta lk) and p a rs n e rvosa. Va rious
re l e a s i n g a n d i n h i b iti n g h o r m o n e s sto red i n the median e m i n e n c e a r e tra n sferre d , via the hyp o p h ys e a l p o rtal syste m , to
the p a rs d i sta lis. A D H , a nti d i u reti c h o rm o n e ; GH, g rowth h o r m o n e ; TS H , thyro i d - sti m u l ating h o r m o n e; ACTH, a d r e n o c o rti­
c otro p i c h o rm o n e ; FS H , fo l l i c l e-sti m u lati n g h o rm o n e ; LH, lute i n iz i n g h o r m o n e . I Reprinted with permission from Morton P. Fonta ine D.
Critical Care Nursing. 1 0th ed. Philadelphia. PA: Wolters Kluwer Hea lth/Lippincott Will iams & Wilkins; 201 2:959.)

3. Gonadotrophs constitute about 10% ofthe chromophil population. They produce
FSH and luteinizing hormone (LH) in both sexes, although in men, the latter is
sometimes referred to as i nterstitial cel l-stimulating hormone. Gonadotrophs
are stimulated by gonadotropi n-releasing hormone, also known as LH-releasing
hormone.

b. Chromophobes (Figure 13.3)
(1 ) are parenchymal cells that stain poorly.
(2) appear as small cells under the light microscope; the cells lack (or have only a few)
secretory granules and are arranged close to one another in clusters.

(3) sometimes resemble degranulated chromophils in the electron microscope, suggesting
that they may represent different stages in the life cycle of various acidophil and
basophil populations.
(4) may also represent undifferentiated cells that are capable of differentiating into various

types of chromophils.

c. Fol l iculostellate cells
(1 ) are numerous in the pars distalis and lie between the chromophils and chromophobes.
(2) possess long processes that form gap junctions with processes of other folliculostellate
cells.

(3) produce many peptides that are thought to regulate the production of pars distalis
hormones via a paracrine effect.


l!iitJ'!1tilU Endocrine System

225

F I G U R E 1 3.3. A l i g ht m i c ro g r a p h of c e l l s i n the p a rs d ista l i s of th e a d e n o hy p o p hysis. The two typ es of c h ro m o p h i l c e l l s a r e

e a s i ly i d e ntifi e d u s i n g th e tri c h ro m e sta i n . B a s o p h i l s ( B ) sta i n b l u e , a n d a c i d o p h i l s (A) sta i n r e d . C h r o m o p h o b e s ( C ) are
smaller a n d s h ow l ittle a ffin ity for the sta i n . M a ny e ryth ro cytes (red b l o o d cells [ R B Cs]) a r e present i n th e c a p i l l a ries ( X 300).

2. The pars intermedia lies between the pars distalis and pars nervosa.
a. It contains many colloid-containing cysts ( Rathke cysts) that are lined by cuboidal cells.
b. It also possesses basoph i l i c cel ls, which sometimes extend into the pars nervosa. These
cells secrete the prohormone POMC, which is cleaved to form ACTH, l i potropin, and MSH.
I n humans, M S H acts t o induce melanocytes t o produce melanin and may act i n various
ways to modulate inflammatory responses throughout the body, and it may play a role in
controlling stores of body fat.
3. The pars tubera lis surrounds the cranial part of the infundibulum (hypophyseal stalk).
a. It is composed of cuboidal basophilic cel ls, arranged in cords along an abundant capillary
network.

b. Its cells may secrete FSH and LH, but this has not been confirmed.

CLI N I CAL
CONSID ERATIO N S

Pituitary adenomas a re common tumors o f the a nte rior p itu ita ry.
1 . They e n l a rg e a n d ofte n s u p p ress s e c reti o n s by the re m a i n i n g p a rs
d i sta lis c e l l s.

2. These tu m o rs fre q u e ntly d e stroy s u r ro u n d i n g bone and n e u ra l tiss u e s and a r e treated by
s u rg i c a l remova l .

B. The neurohypophysis (Figures 1 3 . 1 and 13.2; Table 1 3 . 1 ) i s also called the posterior pituitary gland.
I t originates from a n evagination o f the hypothalamus and i s divided into the infundibulum, which
is continuous with the hypothalamus, and the pars nervosa, or main body of the neurohypophysis.

1. Hypothalamo-hypophyseal tract
a. contains the unmyelinated axons of neurosecretory cells whose cell bodies are located in
the supraoptic and paraventricular nuclei of the hypothalamus.
b. transports oxytocin and antidiuretic hormone (AD H; vasopressin), each bound
to neurophysin (a binding protein specific for each hormone) to the pars nervosa
(see Table 13.2). Oxytocin binds to neurophysin I, whereas ADH binds to neurophysin II.
Additionally, acetylcholine and adenosine triphosphate (ATP) are transported to the pars
nervosa by the axons that compose the hypothalamo-hypophyseal tract.


226

BRS Cell B iology and H istology

t a b I e

13.1

Cell

Physiolo g i c a l Effects of Pituita ry H o rmones
Hormone

M a j o r Function

Hormones released by the pars distalis
Acidophils

Som atotrophs

Som atotro pin ( g rowth
hormone)

I n c re a s e s m eta bolism in m o st c e l ls; i n d i r e ctly sti m u lates
e p i phys e a l p l ate, g rowth of long bones via p rod u ction of
i n s u l i n - l i ke g rowth fa ctors I , I I

M a m m otro p h s
(La ctotro p h s )

Prola ctin

Deve l o p m e nt o f m a m m a ry g l a n d d u ring p re g n a n cy, m i l k
synth esis d u ri n g l a ctati o n

C o rtic otro p h s

P O M C whose
by-produ cts are
ACTH, M S H , a n d
l i p otro p i n

ACTH sti m u lates g l u c o c o rti coid s e c reti o n by z o n a
fa s c i c u lata c e l l s of a d r e n a l c o rtex;
M S H sti m u l ates m e l a n o cytes to m a n ufa cture m e l a n i n
p i g m e nts;
Lipotro p i n also sti m u l ates m e l a n o cytes to m a n ufacture
m e l a nin, but also m o b i l izes l i p i d s by i n d u c i n g l i p o lysis
and the fo rmation of ste roids.

G o n a d otro p h s

FSH

LH o r i nte rstiti a l
c e l l-sti m u lating
hormone

Sti m u l ates g rowth of s e c o n d a ry ova rian fo l l i c les, estrog e n
s e c retion i n wo m e n ; sti m u l ates s p e rmato g e n esis via
produ ction of a n d ro g e n - b i n d i n g p rote i n i n S e rto l i c e l l s
in men
Ovulation, fo rmation o f c o r p u s l ute um, a n d progesterone
s e c retion i n wo m e n ; testoste ro n e synth esis by Leyd ig

cells of testis i n men

TSH

Sti m u l ates synth esis a n d release of T3, T4 by fo l l i c u l a r cells

Basophi/s

Thyrotro phs

Hormones released by the pars nervosa

N e u rosec retory c e l l s of
hypoth a l a m u s ( p ri m a rily
in the pa raventri c u l a r
nucleus)
N e u rosec retory c e l l s of
hypoth a l a m u s ( p rima rily
in the s u p ra o ptic n u c l e u s )

Oxyto c i n

I n d u c e s c o ntra ction of smooth m u s c l e in wa l l of ute rus at
p a rtu rition and i n myo e p ith e l i a l c e l l s of m a m m a ry g l a n d
d u ring n u rsing

AOH

R e n d e rs kidney c o l l e cting tu b u l e s p e r m e a b l e to wate r,
wh ich is resorbed to p ro d u c e a c o n c e ntrated u rine;

c o n stri cts smooth m u s c l e i n wall of a rte rioles

POMC. pro-opiomelanocortin; ACTH. adrenocorticotropic hormone; MSH. melanocyte-stimu lating hormone; FSH. fol l icle-stimu lating hormone; LH.
l uteinizing hormone; TSH, thyroid-sti mulating hormone; ADH. antidiuretic hormone.

2. Pars nervosa
a. contains the distal ends of the hypothalamo-hypophyseal axons and is the site where the
neurosecretory granules in these axons are stored in accumulations known as Herring
bodies.
b. releases oxytocin and ADH into fenestrated capillaries in response to nerve stimulation.
3. Pituicytes
a. occupy approximately 25% of the volume of the pars nervosa.
b. are glial-like cells that support axons in this region.
c. possess numerous cytoplasmic processes and contain lipid droplets, intermediate
filaments, and pigments.

D i a b etes Insi p i d us
D i a b etes i n s i p i d u s resu lts fro m i n a d e q u ate a m o u nts of AD H ; it is
d i s c ussed i n C h a pter 18 V C C l i n i c a l C o n s i d e rati o n s .

C. Vascularization o f t h e p ituitary g l a n d
1. Arterial supply is from two pairs of blood vessels derived from the internal carotid artery.
a. The right and left superior hypophyseal arteries serve the pars tuberalis, infundibulum, and
median eminence.
b. The right and left inferior hypophyseal arteries serve mostly the pars nervosa.


l!iitJ'!1tilU Endocrine System
t a b I e

13.2

227

Hormones of th e Hypoth a l a m u s

Hormone

Nucleus

Primary Functions

Oxyto c i n

P ri m a ri ly the pa raventri c u l a r
nucleus

I n d u c e s c o ntraction of s m o oth m u s c l e i n wa l l
of ute rus at p a rtu rition a n d i n myo e p ith e l i a l
c e l l s o f m a m m a ry g l a n d d u ring n u rs i n g

AD H; vasopressin

P ri m a rily t h e s u p r a o ptic n u c l e u s

R e n d e rs kidney c o l l e cti n g tubules p e r m e a b l e
t o wate r, w h i c h is r e s o r b e d t o prod u c e
a c o n c e ntrated u rine; c o n stri cts s m o oth
m u s c l e i n w a l l of a rterioles

CRH

Arcu ate, m e d i a l pa rave ntri c u l a r,
a n d pe riventri c u l a r n u c l e i

Induces the release of POMC by the
c o rti c otro p h s of the a nterior pitu ita ry

Dopamine

Arcu ate n u c l e u s

I n h i b its prola ctin release by m a m m otro p h s
( l a ctotro p h s ) of the a nte ri o r pitu ita ry

GnRH

Arcu ate, d o rsal, p a rave ntri c u l a r,
a n d ve ntro m e d i a l n u c l e i

I n d u c e s the release of LH a n d FSH by
g o n a d otro p h s of the a nterior pitu ita ry

Som atostati n

Arcu ate n u c l e u s

I n h i b its som atotro p i n release by the
som atotro phs of the a nterior p itu ita ry

S o m atotropin-releasing factor ( S R H )
( a l s o kn own a s g rowth h o r m o n e­
releasing fa ctor, G H R H )

Arcu ate n u c l e u s

I n d u c e s the release of som atotropin ( g rowth
h o r m o n e ) by the som atotro p h s of the
a nterior p itu ita ry

TRH

D o rsal, pa rave ntri c u l a r,
a n d ve ntro m e d i a l n u c l e i

I n d u c e s the release of TSH by the thyrotro phs
a s well a s prola ctin by the m a m m otro p h s
( l a ctotrophs) of the a nterior pitu ita ry

ADH, antidiuretic hormone; CRH, corticotropi n-releasing hormone; PDMC, pro-opiomelanocortin; GnRH, gonadotropin-releasing hormone; LH, luteinizing
hormone; FSH, fo l l i cle-stimu lating hormone; SRH, somatotropi n-releasing hormone; GHRH, g rowth hormone-releasing hormone; TRH, thyrotropin­
releasing hormone; TSH, thyroid-stimulating hormone.

2. Hypophyseal porta l system (Figures 1 3 . 1 and 13.2)
a. The primary capillary p l exus consists of fenestrated capillaries coming off the superior
hypophyseal arteries.
(1 ) This plexus is located in the median eminence, where stored hypothalamic
neurosecretory hormones enter the blood.
(2) It is drained by hypophyseal portal vei ns, which descend through the infundibulum
into the adenohypophysis.

b. The secondary capil lary plexus consists of fenestrated capillaries derived from the
hypophyseal portal veins. This plexus is located in the pars distal is, where neurosecretory
hormones leave the blood to stimulate or inhibit the parenchymal cells.

CLI N I CAL
CONSID ERATIO N

S h e e h a n Synd rome
Sheehan syndrome is n e c rosis of the a nteri o r p itu ita ry g l a n d due to a

s u d d e n re d u ctio n i n b l o o d p re s s u re of th e n ewborn as a result of p o st­
p a rtum h e m o rrh a g e . Th e b u l k of the a nte rior p itu ita ry b e c o m e s n e c roti c a n d o n ly th e p e r i p h e r a l
p a r e n c hy m a l c e l l s re m a i n h e a lthy a n d vi a b l e . The f u n cti o n a l ity o f the a d e n o hy p o p hysis d e p e n d s o n
th e seve rity o f t h e n e c roti c eve nt; the wid e r t h e p a r e n c hym a l d e stru cti o n , the l e s s fun cti o n r e m a i n s .
I nte resti n g ly, the n e u rohypop hysis is u s u a lly u n affe cte d b e c a u s e i t h a s a d iffe rent b l o o d s u p p ly.

Hemosiderosis
Patie nts affl i cted with hemochromatosis ( i ron overl oad), wh eth e r a s a fun cti o n of h e re d ity or
a c q u i re d due to m u lti p l e tra n sfusions, p re s e nt with iron d e posits i n the p itu ita ry g l a n d , e s p e c i a l ly i n
the g o n a d otro p h s . This c o n d ition is known a s hemosiderosis a n d is fortu n ately tre ata b l e e ith e r b y
p h l e b otomy o r by c h e l ati n g th e iron with o n e of the ava i l a b l e c h e lati n g a g e nts i n the p h a rm a c e uti c a l
a r m a m e nta ri u m .


228

BRS Cell B iology and H istology

D. Regulation of the pars dista lis (Figures 13.1 and 13.2)
1. Neurosecretory cells in the hypothalamus synthesize specific hormones that enter the

hypophyseal portal system and stimulate or inhibit the parenchymal cells of the pars distalis
(see Table 13.2).
2. The hypothalamic neurosecretory cells in turn are regulated by the level of hormones in the
blood (negative feedback) or by other physiological (or psychological) factors.
3. Some hormones (e.g., thyroid hormones, cortisol) exert negative feedback on the pars distalis
directly.

The thyroid gland is composed of two lobes connected by an isthmus. It is surrounded by a dense
irregular collagenous connective tissue capsule, in which (posteriorly) the parathyroid glands are
embedded. The thyroid gland is subdivided by capsular septa into lobules containing follicles. These
septa also serve as conduits for blood vessels, lymphatic vessels, and nerves.
A. Thyroid fol l i cles are spherical structures filled with colloid, a viscous gel consisting mostly of
iodinated thyrog lobulin (Figure 13.5)
1. Surrounding the colloid within each follicle is a single layer of epithelial cells, called follicular
cel ls. In addition, one or more parafo l l icular cells occasionally lie sandwiched between the
follicular cells. Both of these parenchymal cell types rest upon the basal lamina surrounding
the follicle, which separates them from the abundant network offenestrated capillaries in the
connective tissue.
2. Function. Thyroid follicles synthesize, store, and release thyroid hormones.
B. Fol l icular cells (Figure 13.6)

1. Structure
a. Follicular cells are normally cuboidal, but they become columnar when stimulated and
squamous when inactive.

b. They possess a distended rough endoplasmic reticulum (RER) with many ribosome­
free regions, a supranuclear Golgi complex, many lysosomes, and rod-shaped
mito chondria.
c. Follicular cells also contain many small apical vesi cles, which are involved in the transport
and release of thyroglobulin and enzymes into the colloid.

d. They possess short, blunt microvilli that extend into the colloid.
2. Synthesis and release of the thyroid hormones thyroxine (T4) and tri iodothyronine (T3) occur
by the sequence of events illustrated in Figure 13.7. These processes are evoked by TSH, which
binds to G protein-linked receptors on the basal surface of follicular cells.

CLI N I CAL
CONSID ERATI O N S

G raves disease i s c h a ra cterized by a d iffus e enlargement o f t h e thyroid
gland and protrusion of the eyeballs ( exo p hth a l m i c g o iter).

1. This d i s e a s e is a s s o c iated with th e prese n c e of c o l u m n a r-sh a p e d thyro i d fo l l i c u l a r c e l ls,
exc essive p rod u ction of thyro i d h o r m o n e s, a n d d e c re a s e d a m o u nts of fo l l i c u l a r c o l l o i d .

2. It is c a u s e d b y th e b i n d i n g o f a uto i m m u n e i m m u n o g l o b u l i n G ( l g G ) a nti b o d i e s t o TS H re c e pto rs,
w h i c h sti m u l ates th e thyro id fo l l i c u l a r c e lls. Additi o n a l ly, infl a m m ato ry c e lls, s u c h as T c e l ls,
n e utro p h i ls, and m a c ro p h a g es, inva d e the c o n n e ctive tissues of th e retro-orbita l r e g i o n a n d
r e l e a s e cyto ki n e s that a ctivate fi b ro b l a sts n ot o n ly t o i n c re a s e th e i r prod u ctio n o f p rote o g ly c a n s
b ut a l s o t o d iffe re ntiate i nto f a t c e l l s . S i n c e p rote o g ly c a n s re a d i ly attra ct N a + i o n s wh i c h attra ct
wate r m o l e c u l es, th e c o n n e ctive tissue vo l u m e i n c re a ses; m o reover, th e a d d itio n a l n u m b e r of
fat c e l l s also a cts to i n c re a s e th e vo l u m e of the retro-o rb ita l c o n n e ctive tissue, putti n g i n c re a s e d
press u re o n th e b a c k o f the eye b a l l , p u s h i n g i t fo rwa rd, res u lti n g i n p rotru sion of the eye.


l!iitJ'!1tilU Endocrine System

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Suprarenal

Cortex

G land

Zona reticularis

Zona fasciculata

:---'i'----- Ne u roglial
cell

P i nealocytes

F I G U R E 1 3.4. A d i a g ra m showing features of th e thyro id, p a rathyro i d , a d re n a l , and p i n e a l g l a n d s . ( From Gartner LP, H iatt JL. Color
Atlas of Histology.

5th ed. Baltimore. M D : Lippincott W i l l iam & Wilki ns; 2009:207 )

C. Parafo l l icular cells are also called clear (C) cells because they stain less intensely than thyroid
follicular cells (Figures 13.5 and 13.8).
1. Parafollicular cells are present singly or in small clusters of cells between the follicular cells
and basal lamina.
2. These cells belong to the population of O N ES cel ls, previously known as amine precursor
uptake and d ecarboxylation (APUD) cells, or enteroendocrine cells.


230

BRS Cell B iology and H istology

FIGURE 13.5. A l i g ht m i c ro g r a p h showing fo l l i c l e s with i n the thyro i d g l a n d . Each fo l l i c l e is s u rro u n d e d by a layer of

fo l l i c u l a r c e l l s (F) and c o nta i n s a c e ntra l c o l l o i d -fi l l e d re g i o n ( C ) . The fo l l i c u l a r c e l l s synth esize a n d s e c rete thyro i d
h o r m o n e s b o u n d with i n a l a rg e p rote i n m o l e c u l e , thyro g l o b u l i n , w h i c h m a kes u p m ost o f the c o l l o i d . A s e c o n d typ e o f
e n d o c ri n e c e l l , t h e pa rafo l l i c u l a r c e l l ( P ). i s a l s o p r e s e nt i n th e thyro i d g l a n d . It h a s n o c o ntact with the c o l l o i d a n d is often
fo u n d i n s m a l l c l u sters at o r n e a r the b a s a l s u rfa c e s of th e fo l l i c u l a r c e lls. The pa rafo l l i c u l a r c e l l synth esizes c a l c ito n i n
a n d re l e a s e s i t i nto the r i c h n etwork of c a p i l l a ries ( arrows) existi n g betw e e n th e fo l l i c l e s ( X 1 50).

FIGURE 13.6. E l e ctron m i c ro g r a p h of thyro i d fol l i c u l a r c e l ls. Two l a rg e colloid d r o p l ets ( C D ), a d iste n d e d ro u g h e n d o p l a s m i c

reti c u l u m ( R E R ) with m a ny ribosome-free r e g i o n s , a n d a G o l g i a p p a ratu s ( G ) a re o b s e rved. M i c rovilli (MV) exten d i nto th e
l u m e n of a fo l l i c l e - c o nta i n i n g c o l l o i d ( C ) . Also present a r e mito c h o n d ri a ( M ), a n u c l e u s ( N ), a n d a d e s m o s o m e ( D ) ( X 7,500).


l!iitJ'!1tilU Endocrine System

231

Iodinated thyroglobu l i n
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bound to receptor

A. Thyro g l o b u l i n is synth esized

l i ke oth e r s e c reto ry p rote i n s . Circ u l ati n g iodide o-l is a ctively tra n s p o rted i nto th e cytos o l via s o d i u m - i o d i d e sym p o rt­
e rs, so that the i o d i d e c o n c e ntrati o n in the folli c u l a r c e l l s b e c o m e s 20 to 30 ti m e s g reater th a n it i s in the b l o o d . I o d i d e
l e aves th e fo l l i c u l a r c e l l t o e n t e r t h e c o l l o i d via pendrin, a n i o d i d e- c h l o r i d e tra n s p o rter. A t t h e s a m e ti m e , n o n i o d i n ated
thyroglobulin, p a c k a g e d with th e e n zyme thyroid peroxidase i s a l s o b e i n g r e l e a s e d into the c o l l o i d . At th e c o l l o i d
fo l l i c u l a r c e l l i nte rfa c e , thyro i d p e roxi d a s e oxidizes th e i o d i d e to f o r m i o d i n e ( I ) a n d i o d i n ates tyros i n e re s i d u e s o n t h e
thyro g l o b u l i n m o l e c u l e , form i n g m o n o i o d otyro s i n e a n d d i i o d otyros i n e r e s i d u e s ; the refo re, i o d i n ation o c c u rs m o stly a t
the a p i c a l p l a s m a m e m b r a n e . A rearra n g e m e nt, by oxid ative c o u p l i n g , of the n e i g h b o ri n g i o d i n ated tyrosine res i d u e s
o f thyro g l o b u l i n i n the c o l l o i d p r o d u c e s tri iodotyrosine (T3) a n d tetraiodotyrosi ne (14, thyroxine). B. B i n d i n g o f
thyro id -sti m u l ati n g h o r m o n e t o r e c e ptors o n th e b a s a l s u rfa c e sti m u l ates fol l i c u l a r c e l l s t o b e c o m e c o l u m n a r a n d to form
a p i c a l p s e u d o pods, w h i c h e n g ulf c o l l o i d by e n d o cyto sis. Afte r th e c o l l o i d d ro p l ets fuse with lysosomes, c o ntro l l e d hydro­
lysis of i o d i n ated thyro g l o b u l i n l i b e rates T3 and T4 i nto the cyto s o l . These h o r m o n e s m ove b a s a lly and are re l e a s e d b a s a l ly
to e nte r the b l o o d stre a m a n d lym p h atic vessels, wh e re they b i n d with the c a rr i e r p rote i n , thyroxi n e - b i n d i n g g l o b u l i n , that
ferries the h o r m o n e s to th e i r ta rget c e l l s . ( Adapted with perm ission from Junqueira LC. Carneiro J. Kel l ey R O . Basic Histology. 9th ed. Stamford.
CT: Appleton & Lange; 1 998:403, and from Fawcett OW. Bloom and Fawcett. A Textbook of Histology. 1 2th ed. New York, NY: Chapman & Hall; 1 994:496.)
F I G U R E 1 3.7. Synth esis a n d re l e a s e of T4 a n d T3 by fo l l i c u l a r c e l l s of the thyro i d g l a n d .

3. They possess elongated mitochondria, substantial amounts of RER, a well-developed Golgi
complex, and many membrane-bound dense secretory granules.
4. They synthesize and release calcitonin, a polypeptide hormone, in response to high blood
calcium levels.
D. Physiological effects of thyroid hormones
1. T4 and T3 act on a variety of target cells. These hormones increase the basa l metabolic rate and
thus promote heat production. They have broad effects on gene expression and the induction
of protein synthesis. T4 has a much longer half-life (approximately 6 days vs. less than a day)
but is much less active than T3. Both hormones have to enter the nucleus to perform their
function.
2. Calcitonin functions primarily to lower blood calcium levels by inhibiting bone resorption by
osteoclasts.

CLI N I CAL

CONSID ERATIO N S

Simple goiter (enlargement o f the thyro id g l a n d ) is c a u s e d b y i n s uffi c i e nt
i o d i n e ( < 1 0 � g/day) in the d i et.

1 . It is u s u a l ly n ot asso c i ated with e ith e r hyp e rthyro i d i s m or hyp othyroi d i s m .
2 . S i m p l e g o iter is treated by a d m i n istratio n of d i eta ry i o d i n e .


232

BRS Cell B iology and H istology

F I G U R E 13.8. E l e ctron m i c ro g r a p h of a p a rafo l l i c u l a r cell ( c l e a r cell, C c e l l ) i n the thyro i d g l a n d . This cell l i e s b etwe e n the
fo l l i c u l a r cells (F) with i n the basal l a m i n a ( B L) e n ve l o p i n g the fo l l i c l e . Its n u c l e u s (N) d i s p l ays a n u c l e o l u s ( arrow) , and its
cyto p l a s m possesses e l o n g ated m ito c h o n d ria ( M ) . In response to h i g h levels of c a l c i u m in the b l o o d , the p a rafol l i c u l a r
c e l l r e l e a s e s the h o r m o n e c a l c ito n i n by exocyto sis of t h e d e n s e g r a n u l e s ( G ) i n its cyto p l a s m . T h e c a l c ito n i n e nters
n e a rby fe n e strated c a p i l l a ri e s and l owers b l o o d c a l c i u m levels by i n h i b iti n g o ste o c l a st b o n e reso rpti o n thro u g h o ut the
body ( X 7,000).

A. Overview
1. The parathyroid glands are four small glands that lie on the posterior surface of the thyroid
gland, embedded in its connective tissue capsule.
2. They have a parenchyma composed of two types of cells, ch ief cells and oxyphil cel ls.
3. They are supported by septa from the capsule, which penetrate each gland and also convey
blood vessels (Figure 13.4) into its interior.
4. They become infiltrated with fat cells in older persons, and the number of oxyphil cells also
increases.
B. Chief cells are small basophilic cells arranged in clusters (Figure 13.9).

1. Chief cells form anastomosing cords, surrounded by a rich, fenestrated capillary network.
2. These cells possess a central nucleus, a well-developed Golgi complex, abundant RER, small
mitochondria, glycogen, and secretory granules of variable size.


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233

F I G U R E 1 3.9. A l i g ht m i c ro g r a p h of the p a rathyroid g l a n d . C h i ef c e l l s ( C ) a re s m a l l b a s o p h i l i c c e l l s a r r a n g e d in c o rd s a l o n g

c a p i l l a ri e s . T h e y synth esize a n d s e c rete pa rathyro i d h o r m o n e t h a t r a i s e s b l o o d c a l c i u m l e v e l s prima rily by m o b i l izing
c a l c i u m from the bone. Oxy p h i l cells ( 0 ) a r e a l s o present i n the p a rathyroid g l a n d . They a re a c i d o p h i l i c , much l a rg e r
th a n t h e c h ief c e lls, a n d few i n n u m b e r, b u t they i n c re a s e i n n u m b e r with a g e . Oxy p h i l s c o nta i n m a ny l a rg e e l o n g ated
m ito c h o n d ri a , but the fun cti o n of th e s e c e l l s is not known (X 1 50).

3. Function. They synthesize and secrete parathyroid hormone (PTH, or parathormone), which
raises blood calcium levels. High blood calcium levels inhibit the production of PTH. The
hormone acts on osteoclasts (see Chapter 7 II C 4 and II J) and also induces the decrease in
calcium excretion by the thick ascending limb of Henle loop.
4. Mechan ism. The cell membrane of chief cells possesses a transmembrane Ca2 + receptor
(CaSR) that binds calcium ions. In the presence of calcium ions, CaSR activates G proteins
that shut off the release of parathormone, whereas if calcium ions do not bind to CaSR, the
inhibitory activity of the G protein is suppressed and the chief cell releases parathormone.
C. Oxyph i l cells are large, eosinophilic cells that are present singly or in small clusters within the
parenchyma of the gland (Figure 13.9).
1. Oxyphil cells possess many large, elongated mitochondria, a poorly developed Golgi complex,
and only a limited amount of RER.
2. Their function is not known.
D. PTH functions primarily to increase blood calcium levels by indirectly stimulating osteoclasts to

resorb bone. In concert with calcitonin, the hormone produced and released by the C cells of the
thyroid gland, PTH provides a dual mechanism for regulating blood calcium levels. A near absence
of PTH (hypoparathyroidism) may be caused by accidental surgical removal of the parathyroid
glands, which leads to tetany, characterized by hyperexcitability and spastic skeletal muscle
contractions throughout the body.

CLI N I CAL
CONSID ERATIO N S

Hyperparathyroid ism is overa ctivity o f the p a rathyroid g l a n d s,
resulti n g in excess s e c retio n of PTH a n d c o n s e q u e nt b o n e reso rpti o n
( s e e C h a pte r 7 II J 1 ) .

1 . Hyperpa rathyro i d i s m is a s s o c i ated with high blood calcium l evels, wh i c h m ay l e a d to
d e position of c a l c i u m s a lts in the k i d n eys a n d the w a l l s of b l o o d vessels.

2. It may b e c a u s e d by a benign t u m o r of th e p a rathyroid g l a n d s .


234

BRS Cell B iology and H istology

Adrenal glands lie embedded in fat at the superior pole of each kidney. They are derived from two
embryonic sources : the ectodermal neural crest, which gives rise to the adrenal medulla, and the
mesoderm, which gives rise to the adrenal cortex. The adrenal glands are invested by their own
collagenous capsule.
A. The adrenal cortex ( Table 13.3) contains parenchymal cells that synthesize and secrete but do not
store various steroid hormones. The production of steroid hormones is dependent on a specific
protein, steroidogenic acute reg ulatory protei n (StAR) that facilitates the transport of cholesterol

across the outer membranes of mitochondria. The adrenal cortex is divided into three concentric
histologically recognizable regions: the zona g lomerulosa, zona fasciculata, and zona reticularis
( Figure 13. 10) .

1 . Zona glomerulosa
a. synthesizes and secretes mi neralocorticoids, mostly aldosterone and some deoxycortico­
sterone. Hormone production is stimulated by angiotensin II and ACTH.
b. is composed of small cells arranged in arch-like cords and clusters. These cells have a few
small lipid droplets, an extensive network of smooth endoplasmic reticulum (SER), and
mitochondria with shelf-like cristae.

2. Zona fasciculata
a. synthesizes and secretes g l ucocorticoids, namely cortisol and corticosterone. Hormone
production is stimulated by ACTH ( Figure 13. 1 1) .

b. is composed o f columns of cells and sinusoidal capillaries oriented perpendicularly t o the
capsule.

c. cells contain many lipid droplets and ( in tissue sections ) appear so vacuolated that they are
called spongiocytes ( Figure 13. 12). These cells also possess spherical mitochondria with
tubular and vesicular cristae, SER, RER, lysosomes, and l ipofuscin pigment g ranules.
3. Zona reticularis
a. synthesizes and secretes weak androgens ( mostly dehydroepiandrosterone and some
androstenedione) and perhaps small amounts of glucocorticoids. Hormone production is
stimulated by ACTH.

b. is composed of cells, arranged in anastomosing cords. Many large lipofusc in pigment
g ranules are common in these cells ( Figure 13. 12) and are believed to represent lipid­
containing residues oflysosomal digestion.
t

a

b I

e

13.3

Adrenal G l a n d Cells and H o rmones
H ormone

Function

Zona g l o m e ru l osa

M i n e r a l o c o rti c o i d s (mostly a l d oste ron e )

R e g u l ate e l e ctro lyte, wate r b a l a n c e via effect
on c e l l s of re n a l tu b u l e s

Zona fa s c i c u l ata

G l u c o c o rti c o i d s ( c o rtisol, c o rti c o ste rone)

R e g u late c a rbohyd rate meta b o l i s m b y
p romoting g l u c o n e o g e nesis; promote
breakd own of proteins, fat; a nti·infl a m m ato ry
properties; s u p press i m m u n e response

Zona reti c u l a ris

We a k a n d ro g e n s ( d e hyd roepiand roste rone,
a n d roste n e d i o n e )

Promote m a s c u l i n e c h a ra cteristi c s

E p i n e p h ri n e

Fig ht·o r·fl i g ht response; i n c reases h e a rt rate
and fo rce of contra ction; relaxes b ro n c h i o l a r
smooth m u s c l e ; promotes glyc o g e n o lysis
and l i p o lysis
Littl e effe ct on c a rd i a c o utp ut, rarely u s e d
c l i n i c a l ly

Cell
Adrenal cortex

Adrenal medulla

C h rom affi n c e l l s

N o r e p i n e p h ri n e


F I G U R E 13.10. A l i g ht m i c ro g r a p h of the a d r e n a l g l a n d s h ow i n g the d iffe re nt regions of the c o rtex ( CTX) a n d a p o rti o n of
the m e d u l l a ( M E D ) . C e l l s in the outermost z o n a g l o m e ru l o s a (ZG ) a r e a r r a n g e d in c l u sters a n d s e c rete m i n e ra l o c o rti c o i d s ;
c e l l s i n th e m i d d l e z o n a fasc i c u l ata ( Z F ) a r e a rra n g e d i n c o rd s between s i n u s o i d a l c a p i l l a ri e s a n d s e c rete g l u c o c o rti c o i d s
a n d a s m a l l a m o unt o f a n d ro g e ns; a n d c e l l s o f the i n n e rm o st z o n a reti c u l a ri s ( Z R ) a re a rr a n g e d i n a n a sto m o s i n g c o rd s

a n d s e c rete a n d ro g e n s a n d s m a l l a m o u nts of g l u c o c o rti c o i d s . C e l l s i n the a d r e n a l m e d u l l a ( M ), c a l l e d c h ro m affi n c e l ls,
synth esize, sto re, and s e c rete e p i n e p h ri n e and n o r e p i n e p h r i n e ( X 1 6).

Gonadal axis

Adrenal axis

Hypothalamus

C

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F I G U R E 13.11. R e g u l ati o n of g l u c o c o rti c o i d s e c reti o n by the a d r e n a l c o rtex via sti m u lati o n by c o rtic otro p i n - r e l e a s i n g

h o r m o n e a n d a d re n o c o rtic otro p i c h o r m o n e (ACTH ) a n d the n e g ative feed b a c k of c o rtis o l at b oth the p itu ita ry a n d t h e
hypoth a l a m i c l e v e l s . G n R H , g o n a d otro p i n - r e l e a s i n g h o r m o n e ; C R F, c o rtic otro p i n - r e l e a s i n g fa cto r; FSH, fo l l i c l e-sti m u l ating
hormone; LH, lute i n i z i n g hormone. (Reprinted with permission from Rosenfeld G. Loose D . BRS Pharmacology. 5th ed. Baltimore. M D : Wolters
Kl uwer Hea lth/Lippi ncott Williams & Wilkins; 2009:21 8 )

235


236

BRS Cell B iology and H istology

!'

.

F.Z::.\
.

F I G U R E 13.12. C e l l s of the zona fa s c i c u l ata a n d z o n a reti c u l a ri s a re shown in this very low-power e l e ctron m i c ro g r a p h . Zona
fa s c i c u l ata (ZF) c e l l s a re called s p o n g i o cytes b e c a use of their a p p e a ra n c e, wh i c h is c a used by the extra cti o n of the m a ny
l i p i d d r o p l ets in th e i r cyto p l a s m that h ave b e e n removed thro u g h the process of fixati o n a n d d e hydrati o n . The s p o n g i o cytes
l i e n ext to a rich n etwork of s i n u s o i d a l c a p i l l a ries ( CAP), which have been c l e a red of e rythro cytes by p e rfu s i o n . Zona
reti c u l a ris (ZR) cells are a lso o b s e rved, and a few of them a re fi l l e d with l a rg e li pofu s c i n ( LF) p i g m e nt g r a n u l e s (X 1 ,500).

CLI N I CAL
CONSID ERATIO N S

Addison disease is c h a ra cte rized b y s e c reti o n o f i n a d e q u ate a m o u nts of
a d re n o c o rti c a l h o r m o n e s d u e to d e structi o n of the a d re n a l c o rtex.

1 . A d d i s o n d i s e a s e is m ost often c a u s e d by an a uto i m m u n e d is e a s e or c a n be a s e q u e l a of
tu b e r c u losis.

2. This disease is l ife -th re ate n i n g a n d req u i re s ste roid treatm e nt.

B. The adrenal med u l l a ( Table 13.3) is completely invested by the adrenal cortex. It contains two
populations of parenchymal cells, called chromaffi n cel ls, which synthesize, store, and secrete
the catecholamines epi nephrine ( approximately 80% of chromaffin cells ) and norepinephrine
( approximately 20% of chromaffin cells ) . It also contains scattered sympathetic ganglion cel ls.
1. Chromaffi n cells are large, polyhedral cells containing secretory granules that stain intensely
with chromium salts ( chromaffin reaction ) .

a. Chromaffin cells are arranged in short, irregular cords surrounded by an extensive capillary
network.


l!iitJ'!1tilU Endocrine System

237

b. They are innervated by pregan g l ionic sympathetic (chol inergic) fibers, making these cells
analogous in function to postganglionic sympathetic neurons.

c. They possess a well-developed Golgi complex, isolated regions of RER, and numerous
mitochondria.

d. They also contain large numbers of membrane-bound granules containing one of the
catecholamines, ATP, enkephalins, and chromograni ns, which may function as binding
proteins for epinephrine and norepinephrine.

2. Catecholamine release occurs in response to intense emotional stimuli and is mediated by the
preganglionic sympathetic fibers that innervate the chromaffin cells.

CLI N I CAL
CONSIDERATI O N S

A pheochromocytoma is a tu m o r a ri s i n g i n cate c h o l a m i n e - s e c reti n g
c h ro m affi n c e l l s of the a d re n a l m e d u l l a . The tu m o r is r a r e ; i t is fo u n d i n
b oth sexes, a n d 90% of the ti m e i t is b e n i g n . H oweve r, its s e c retio n o f excessive a m o u nts o f e p i ­
n e p h ri n e a n d n o re p i n e p h ri n e l e a d s t o hypertension ( e p i s o d i c o r s u sta i n e d ), a lth o u g h the pati e nt
m a y r e m a i n a sym pto m ati c . I n c re a s e d levels of c ate c h o l a m i n e s a n d th e i r m eta b o l ites in the u ri n e
a re d i a g n osti c o f p h e o c h ro m o cyto m a . If the tu m o r i s d etected e a rly a n d is s u r g i c a l ly removed, t h e

hyp e rte n s i o n is c o rre cta b l e , b ut i f n ot, p ro l o n g e d a n d s u sta i n e d hyp e rte n s i o n m a y p rove fata l .

C . B l ood supply t o t h e adrenal g l ands i s derived from the superior, middle, and inferior adrenal arteries,
which form three groups of vessels : to the capsule, to parenchymal cells of the cortex, and directly
to the medulla.

1 . Cortical blood supply
a. A fenestrated capillary network bathes cells of the zona glomerulosa.
b. Stra ight, disconti nuous, fenestrated capillaries supply the zona fasciculata and zona
reticularis.

2. Medullary blood supply
a. Venous blood rich in hormones reaches the medulla via the discontinuous fenestrated
capillaries that pass through the cortex.

b. Arterial blood from direct branches of capsular arteries forms an extensive fenestrated
capillary network among the chromaffin cells of the medulla.

c. Medullary veins join to form the suprarenal vein, which exits the gland.

A. Overview (Figure 13.4)
1. The pineal gland projects from the roof of the diencephalon.
2. Its secretions vary with the light and dark cycles of the day, thereby regulating the individual's
circadian rhythm. Although the pineal gland is buried deep within the head, it receives
information about the light and dark conditions from special ganglion cells in the retina of
the eye. These ganglion cells send their information about the presence of daylight via the
retinohypothalamic tract that projects to the suprachiasmatic nucleus of the hypothalamus,
from where information reaches the superior cervical sympathetic ganglion whose
postganglionic sympathetic fibers reach the pineal gland by riding on the tunica adventitia of
blood vessels that supply the pineal.

3. This gland has a capsule formed of the pia mater, from which septa (containing blood vessels
and unmyelinated nerve fibers) extend to subdivide it into incomplete lobules.
4. It is composed primarily of pinealocytes, which constitute approximately 95% of the cells, and
neuroglial cells (interstitial cells), which constitute about 5% of the cells.
5. It also contains calcified concretions (bra i n sand) in its interstitium. The function of these
concretions is unknown, but they increase during short light cycles and decrease during
periods of darkness.


238

BRS Cell B iology and H istology

B. Pinealocytes are pale-staining cells with numerous long processes that end in dilations near
capillaries.
1. Pinealocytes contain many secretory granules, microtubules, microfilaments, and unusual
structures called synaptic ribbons.
2. These cells synthesize and immediately secrete melatonin but almost only at night. During the
day, melatonin synthesis is mostly inhibited.
3. Pinealocytes may also produce arginine vasotocin, a peptide that appears to be an antagonist
of LH and FSH; they also secrete small quantities of serotonin, histamine, and dopamine. Most
of the serotonin manufactured by the pinealocytes is converted to melatonin in a two-step
reaction, the first of which is catalyzed by the enzyme N-acetyltransferase. It is the activity
of this particular enzyme that is inhibited during daylight conditions, thus preventing the
formation of melatonin during daylight.
C. Neurog l i a l ( interstitia l ) cells resemble astrocytes, with elongated processes and a small, dense
nucleus. They contain microtubules and many microfilaments and intermediate filaments.

CLI N I CAL
CONSID ERATI O N S

M e l ato n i n is u s e d t o treat j et l a g a n d s e a s o n a l affe ctive d is o rd e r (SAD),
a n e m oti o n a l response to s h o rte r d a y l i g ht h o u rs d u ri n g the wi nte r.


Review Test
D irections: Each of the numbered items or incomplete statements in this section is followed by
answers or completions of the statement. Select the ONE lettered answer that is BEST in each case.
1. Protein hormones act initially on target cells by
(A) attaching to receptors on the nuclear
(B)
(C)
(D)
(E)

membrane.
attaching to receptors in the nucleolus.
diffusing through the plasma membrane.
attaching to receptors on the plasma
membrane.
attaching to receptors on the rough
endoplasmic reticulum membrane.

5. ACTH is produced by which of the following
cells?

(A) Chromophobes in the pars distalis
(B) Neurosecretory cells in the median
eminence

(C) Basophils in the pars distalis
(D) Neurons of the paraventricular nucleus
in the hypothalamus

(E) Basophils in the pars intermedia

2. Which of the following statements concerning

6. The histological appearance of a thyroid

adrenal parenchymal cells is true?

gland being stimulated by TSH would show
which of the following?

(A) Those of the zona fasciculata produce
androgens.

( B ) Those of the adrenal medulla produce
epinephrine and norepinephrine.

(C) Those of the zona glomerulosa produce
glucocorticoids.

( D ) Those of the cortex contain numerous
secretory granules.

(A)
(B)
(C)

(D)

Decreased numbers of follicular cells
Increased numbers of parafollicular cells
Column-shaped follicular cells
An abundance of colloid in the lumen of
the follicle
(E) Decreased numbers of parafollicular
capillaries

(E) Those of the zona reticularis produce
mineralocorticoids.

3. Characteristics of pinealocytes include
which one of the following?

(A) They produce melatonin.
(B) They resemble astrocytes.
(C) They contain calcified concretions of
unknown function.

(D) They act as postganglionic sympathetic cells.
(E) They are unaffected by dark and light cycles.

7. A 40-year-old woman is diagnosed with
Graves disease. Which of the following
characteristics would be associated with
her condition?

(A)

(B)
(C)
(D)
(E)

Inadequate levels of iodine in her diet
Weight gain
Flattened thyroid follicular cells
Excessive production of thyroid hormones
Increased amounts of follicular colloid

4. Prolactin is synthesized and secreted by
which of the following cells?

8. Which one of the following hormones
lowers blood calcium levels by inhibiting
bone resorption?

(A)
(B)
(C)
(D)
(E)

(A)
(B)
(C)
(D)
(E)

Acidophils in the pars distalis
Basophils in the pars tuberalis
Somatotrophs in the pars distalis
Basophils in the pars intermedia
Gonadotrophs in the pars distalis

Calcitonin
Epinephrine
Parathyroid hormone
Prolactin
T3

239


240

BRS Cell B iology and H istology

9. A 5 1 -year-old man underwent surgery
for removal of a carcinoma on his trachea.
After surgery, he suffered excessive nervous­
ness, muscle cramps, and spasmodic skeletal
muscle contractions in his arms, legs, and feet.
Laboratory tests revealed markedly low levels
of calcium in his blood. Treatment with intrave­
nous calcium and vitamin D led to recovery in
a few weeks. Which one of the following condi­
tions is responsible for these symptoms in this
patient following surgery?

(A)
(B)
(C)
(D)
(E)

Hypothyroidism
Hyperthyroidism
Hypoparathyroidism
Graves disease
Hyperparathyroidism

10. Which one of the following hormones
plays a role in regulating body temperature by
promoting heat production?
(A)
(B)
(C)
(D)
(E)

Calcitonin
Epinephrine
Parathyroid hormone
Prolactin
Triiodothyronine ( T3 )


Answers and Explanations
1 . D. Protein hormones initiate their action by binding externally to transmembrane receptor

proteins in the target-cell plasma membrane. Receptors for some hormones (e.g., TSH,
serotonin, epinephrine) are linked to G proteins; other receptors, including those for insulin
and growth hormone, have protein kinase activity (see Chapter 13 II A).

2. B. Chromaffin cells in the adrenal medulla synthesize and store epinephrine and
norepinephrine in secretory granules, which also contain ATP, chromogranins, and enkepha­
lins. The cortical parenchymal cells of the zona fasciculata produce glucocorticoids, and those
of the zona glomerulosa produce mineralocorticoids. The cortical parenchymal cells do not
store their secretory products and thus do not contain secretory granules (see Chapter 13 VI).

3. A. Pinealocytes, the parenchymal cells of the pineal gland, produce melatonin at night and
serotonin during the day. The pineal gland also contains neuroglial cells that resemble astro­
cytes, and its interstitium has calcified concretions called brain sand (see Chapter 13 VII).
4. A. Prolactin is produced by mammotrophs, one of the two types of acidophils located in the
pars distalis of the pituitary gland. As their name implies, these cells produce a hormone
that regulates the development of the mammary gland during pregnancy and lactation
(see Chapter 13 III A).

5. C. ACTH is produced by corticotrophs, a type of basophil, present in the pars distalis of the
pituitary gland (see Chapter 13 III A) .

6. C. Stimulation of the thyroid gland by TSH causes the follicular cells to become more active
and column shaped. They form apical pseudopods and engulf colloid, which is removed from
the lumen of the follicle by endocytosis and broken down by controlled lysosomal hydrolysis
to yield the thyroid hormones T3 and T4• Parafollicular cells and capillaries do not contain
receptors for TSH (see Chapter 13 IV).

7. D. Graves disease (exophthalmic goiter) results in an enlarged thyroid gland due to stimulation
of the follicular cells to produce an excessive amount of thyroid hormones by binding of auto­
immune antibodies to TSH receptors. Follicular cells actively remove colloid from the lumen

of the follicles. Heat intolerance and weight loss are common, but the disease is not caused by
iodine deficiency (see Chapter 13 IV B Clinical Considerations) .

8. A. Calcitonin lowers blood calcium levels and thus has a n effect antagonistic t o that of parathy­
roid hormone. It is produced by parafollicular cells of the thyroid gland (see Chapter 13 IV D).

9. C. Upon removal of the carcinoma from his neck, the parathyroid glands were also removed
or damaged, causing hypoparathyroidism (a lack of parathyroid hormone that increases blood
calcium). Treatment with calcium (and vitamin D, which aids in its absorption) corrected
these symptoms. The marked neuromuscular irritability in the absence of calcium reveals its
importance in regulating skeletal muscle contraction (see Chapter 13 V D).

1 0. E. Triiodothyronine (T3) and thyroxine (T4) both increase the basal metabolic rate, which
affects heat production and body temperature. These thyroid hormones also have many other
effects (see Chapter 13 IV D).

241


Skin

A. The skin is the heaviest organ, about 16% of the total body weight.
B. It is composed of two layers, the epidermis and the derm is, which interdigitate to form an irregular
contour.
C. A deeper superficial fascial layer, the hypodermis, lies under the skin. This layer, which is not
considered part of the skin, consists of loose connective tissue that binds skin loosely to the
subjacent tissue.
D. The skin contains several epidermal derivatives (sweat glands, hair follicles, sebaceous glands,
nails, and the mammary glands, discussed in Chapter 19). The skin along with its derivatives is
called the integ ument.

E. Function . The skin protects the body against injury, desiccation, and infection; regulates body
temperature; absorbs ultraviolet (UV) radiation, which is necessary for synthesis of vitamin D;
and contains receptors for touch, temperature, and pain stimuli from the external environment.
Additionally, skin acts as an excretory organ via sebaceous, sweat, and apocrine glands.

A. Overview-Epidermis
1 . The epidermis is the superficial layer of the skin. Primarily of ectodermal origin, it is classified
as stratified squamous kerati n ized epithelium. The epidermis is composed predominantly
of kerati nocytes and three other types of cells : melanocytes, Langerhans cel ls, and Merkel

cel ls.
2. The epidermis is constantly being regenerated. Regeneration, which occurs approximately
every 30 days, is carried out by the mitotic activity of keratinocytes, which normally divide at
night.
3. The epidermis has deep downgrowths called epiderma l ridges that interd ig itate with
projections of the dermis (dermal ridges), resulting in a highly irregular interface. Each dermal
ridge is often further subdivided into two secondary dermal ridges by a narrow downgrowth
ofthe epidermis, called an interpapillary peg. Where the epidermis overlies the dermal ridges,
242


l!1lEl'1lttllJ Skin

243

surface ridges are produced. On the fingertips, these surface ridges are visible as fingerprints,
whose configuration is genetically determined and thus unique to each individual.
4. Interestingly, it has been suggested that keratinocytes may participate in immune reactions
because they manufacture and release various signaling molecules, such as interleukins,
interferons, tumor necrosis factors, and colony-stimulating factors that stimulate the immune

system.
B. Layers of the epidermis (Figure 14. 1 , Table 14. 1 )
1 . The stratum basa le (stratum germinativum) i s the deepest layer of the epidermis and
is composed mostly of keratinocytes that are cuboidal to columnar in shape. These
mitotically active cells are attached directly to the basal lamina of the basement membrane
by hemidesmosomes (see Chapter 5 III B) and to each other by desmosomes. These cells
manufacture and house kerati ns 5 and 1 4. The stratum basale also contains melanocytes and

Merkel cells.
2. The stratum spinosum consists of a few layers of polyhedral keratinocytes (prickle cells). Their
extensions, termed "intercellular bridges" by early histologists, are now known to terminate in

desmosomes (see Chapter 5 II A 3). Keratinocytes and their nuclei become larger and flatter a
characteristic of squamous cells. This layer also contains Langerhans cells.
a. Keratinocytes in the deeper aspects of the stratum spinosum are also mitotically active .
b. The malpighian layer (stratum malpighii) consists of the stratum spinosum and stratum
basale. Nearly all of the mitotic activity in the epidermis occurs in this region, and cell
division occurs at night. It is believed that interleukin- 1 and epidermal growth factor
facilitate, whereas transforming growth factor suppresses the mitotic activity of these cells.
c. In the superficial regions of the stratum spinosum, keratinocytes :
(1 ) Contain membrane-coati ng granules (Odland bodies, lamellar bod ies), whose contents
are rich in lipids, especially glycosphingolipids, ceramides, and phospholipids. The
lipid contents of some of these granules are released into the intercellular spaces in
the form of lipid-containing sheets that are impermeable to water and many foreign

substa nces.
(2) Form the intermediate filaments kerati ns 1 and 1 0, replacing the keratin types located
in the cells of the stratum basale. These new keratins form thin bundles of intermediate
filaments, known as tonofi laments.
(3) Form keratohyal i n g ranules, that is, non-membrane-bound structures, whose main

components are the proteins filaggrin and tricohya l i n . The keratohyalin granules
envelop the thin bundles of tonofilaments and cause them to become cross-linked,
thereby forming thick bundles oftonofi brils.

Epidermis

Dermis

FIGURE 1 4.1 . Layers of e p i d e rm i s . The stratum l u c i d u m i s present o n ly i n th i c k skin and i s b e st o b s e rved i n skin from the

palms of the hands a n d the s o l e s of the fe et. M e l a n o cyte s l i e b etwe e n kerati n o cytes i n the stratum b a s a l e . (Adapted with
permission from Ham AH. Cormack DH. Histology. 8th ed. Philadelphia. PA: Lippincott; 1 979:625.)


t a b I e

14.1

Histo l o g i c a l Features of Skin

Divisions

Layers

Characteristics

E p i d e rmis*

Stratum c o r n e u m

The most s u p e rficial layer of e p i d e rmis
M a ny flatte n e d d e a d "cells" c a l l e d s q u a mes, p a c ke d with keratin fil a m e nts
S u rfa c e c e l l s a re s l o u g h e d

Stratum l u c i d u m

I n d isti n ct h o m o g e n e o u s layer of ke ratinocytes; p resent o n ly in th i c k skin
Cells lack n u c l e i and o r g a n e l l e s
Cyto p l a s m is p a c ke d with ke ratin fil a m e nts a n d e l e i d i n

Stratum g r a n u l o s u m

Flatte n e d n u c l e ated ke rati no cyte s a r ra n g e d i n 3-5 1ayers
C e l l s c o nta i n m a ny c o a rse ke ratohya l i n g r a n u l e s associated with tonofi l a m e nts
M e m b ra n e - c oating (wate rp roofi n g ) g r a n u l e s o c c a s i o n a lly present
Present o n ly i n th i c k skin

Stratum s p i n o s u m

Several l ayers of kerati n o cytes, called prickle c e l l s b e c a use they a p p e a r spiny
Desmosomes, a s s o c i ated with tonofi l a m e nts, c o n n e ct cells b etwe e n processes
( i nte r c e l l u l a r bridges)
Ke rati n o cytes c o nta i n m e m b ra n e - c oating (wate rp roofi n g ) granules
Ke rati n o cytes a re m itoti c a l ly a ctive, e s p e c i a lly in deeper laye rs
La n g e r h a n s c e l l s a re also p resent in this layer

Stratum b a s a l e
(stratum g e rminativu m )

D e e pest l a y e r o f epid ermis, com posed o f a s i n g l e l a y e r o f ta l l c u b o i d a l ke ratino cytes

Ke rati n o cytes a re m itoti c a l ly a ctive
M e l a n o cytes and M e rkel c e l l s a re a lso present i n this layer

P a p i l l a ry layer

S u p e rf i c i a l th i n layer of c o n n e ctive tissue that i nterd i g itates with e p i d e r m a l
ri d g e s of the e p i d e rm i s
Forms d e r m a l p a p i l l a e w h e r e M e i s s n e r corpuscles a n d c a p i l l a ry l o o p s may be fo u n d
Conta i n s d e l i c ate c o l l a g e n (type I a n d type I l l ) fi b e rs
Conta ins a n c horing fibrils (type V I I c o l l a g e n ), m i c rofi brils (fibrillin), a n d e l a stic fi b e rs

Reti c u l a r l a y e r

Exte nsive p a rt of the d e rmis, lyi n g d e e p to the p a p i l l a ry layer
Conta i n s thick b u n d les of c o l l a g e n (type I ) fibers and e l a stic fibers
Arte ries, veins, a n d lym p h ati c s a re present
Location of sweat g l a n d s a n d th e i r d u cts, P a c i n i a n corpusc les, and n e rves
In th in skin, conta ins hair follic les, sebaceous glands, and a rrector pili muscles

D e rm i s'

*Stratified squamous keratinized epithelium.
' Dense. irregular connective tissue.

1 . UV rad iation and skin damage
a. Exp o s u re of u n p rote cte d skin to UV l i g ht can c a use h a rmfu l
effe cts to the c e l ls, even i n the a b s e n c e of s u n b u rn .

b. S u n s c re e n with a s u n p rote cti o n facto r ( S PF) rati n g o f 1 5 o r h i g h e r m a y p rote ct a g a i n st UVB
wave l e n gths, b ut offers n o p rote cti o n a g a i n st th e l o n g e r UVA wave l e n gths.

c. R e c e nt stu d i e s h ave sh own that UVA may b e an i m p o rtant facto r i n p h oto a g i n g and may
u lti m ately lead to the d eve l o p m e nt of skin c a n c e r ( e s p e c i a l ly basal c e l l c a rc i n o m a a n d
m e l a n o m a ) l ate r i n l ife.
2. Skin cancers c o m m o n ly o r i g i n ate from c e l l s i n th e e p i d e rm i s . These c a n c e rs u s u a l ly can be
treated s u c c essfu lly if they a re d i a g n o s e d e a rly and s u rg i c a l ly remove d .
a. Basal cell carcinoma a rises from b a s a l ke rati n o cytes.
b. Squamous cell carci noma a rises fro m cells of the stratu m s p i n o s u m .
3 . Malignant melanoma is a form o f s k i n c a n c e r t h a t c a n b e life-th reate n i n g .
a. This form of c a n c e r originates from melanocytes that d ivide, tra nsform, a n d inva d e the d e rmis
a n d the n e nte r th e lym phatic a n d circulato ry systems, metastasizing to a wid e va riety of org a ns.
b. Treatm e nt involves surgical remova l of the skin l e s i o n and re g i o n a l lym p h n o d e s .
Chemotherapy is a l s o re q u i re d b e c a use of the exte nsive m eta sta s e s .
c. A p p roxi m ately 8 6 % o f m e l a n o m a s a re b e l ieved t o b e c a us e d by exp o s u re t o UV ra d i a ­
tio n fro m th e s u n . Alth o u g h m a l i g n a nt m e l a n o m a a c c o u nts fo r l e s s th a n 5 % o f s k i n c a n c e r
c a ses, i t is res p o n s i b l e fo r th e vast m a j o rity o f s k i n c a n c e r d e aths.
d. Th e i n c i d e n c e of m a l i g n a nt m e l a n o m a is ra p i d ly i n c re a s i n g i n the U n ited States . A c c o r d i n g
t o the N ati o n a l C a n c e r I n stitute i n th e y e a r 20 1 4, th e re w i l l b e m o re th a n 76,000 new c a s e s o f
m a l i g n a nt m e l a n o m a , res u lti n g i n m o re th a n 9,000 fata l iti e s i n th e U n ited States .
244


l!1lEl'1lttllJ Skin

245

3. The stratum g ranulosum is the most superficial layer of the epidermis, in which it comprises
three to five layers of flattened keratinocytes that contain even more and bigger accumulations
of keratohyal i n g ranules, thick bundles of keratin filaments (tonofi brils), and membrane­

coati ng granules.
a. Keratohyal i n g ranules stain intensely with basophilic stains, thus are very pronounced in
histological sections.

b. The cytoplasmic aspect of the plasma membrane of keratinocytes in the stratum
granulosum is reinforced by an electron-dense layer 10 to 12 nm thick.

c. Cells in the superficial layers of the stratum granulosum form tight junctions with one
another and with the cells of the stratum lucidum in thick skin and with cells of the stratum
corneum in thin skin. These tight junctions are rich in the membrane protein claudin.
d. The lipid contents of the membrane-coating granules are released into the extracellular
space to form a water-impermeable barrier, preventing nutrients from reaching the
superficial- most layer of cells of the stratum granulosum and those of the strata lucidum
and corneum. Therefore, those cells undergo apoptosis, their organelles die, and the
cells become keratohya lin-tonofi bril-fi lled "hulls:' The impermeable layer also prevents
aqueous fluid from entering the epidermal layers from the external environment.
4. The stratum lucidum is a clear, homogeneous layer just superficial to the stratum granulosum;
it is often difficult to distinguish in histological sections. It is found only in palmar and plantar
skin. This layer consists of keratinocytes that have neither nuclei nor organelles, but contain
an abundance of tonofibrils embedded in keratohyalin, frequently referred to as eleidin.
5. The stratum corneum i s the most superficial layer ofthe epidermis (Figure 14.2). I t may consist
of as many as 15 to 20 layers of flattened, nonnucleated dead "cells" filled with keratohya l i n ­
kerati n complex. These nonviable scale-like structures are called squames (or horny cells),
and have the shape of a 14-sided polygon.
a. The keratohyalin-keratin complex lines the plasma membrane of the stratum corneum cell
and is further strengthened by three proteins i nvolucrin, sma l l pro l ine-rich protein, and
loricrin, thereby establishing a thickened cornified cell envelope.

F I G U R E 1 4.2. A l i g ht m i c ro g r a p h of t h i c k skin f r o m a fi n g e rti p . The b o u n d a ry b etw e e n the e p i d e rm i s ! E l a n d the d e rm i s ! D l

is m a rke d ly i r re g u l a r d u e to e p i d e r m a l d owng rowths, c a l l e d e p i d e r m a l r i d g e s ( e rl, w h i c h inte r d i g itate with d e rm a l r i d g e s ,
c a l l e d d e r m a l p a p i l l a e ( d p l . The e p i d e rm i s ! E l over the fi n g e rtips is v e ry t h i c k d u e t o its stratum c o r n e u m ( S C I . w h i c h forms
s u rfa c e ridges that a re visible a s fi n g e r p rints. Sweat g l a n d d u cts (sdl p e n etrate the base of the e p i d e r m a l ridges (at the
tips of the interp a p i l l a ry pegsl and trave l thro u g h all of the e p i d e r m a l layers, i n c l u d i n g th e stratum c o r n e u m ( a rrowheadl
to re l e a s e sweat from the body. M e i s s n e r c o r p u s c l e s ( a rrowl a n d c a p i l l a ry l o o p s a re present in the d e r m a l p a p i l l a e of the
p a p i l l a ry layer of d e rmis, whereas th i c k c o l l a g e n fi b e rs (cfl and larger blood vessels a r e fo u n d i n its reti c u l a r layer ( X 1 6l.