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2. Describe microscopic anatomy of the pituitary as the central endocrine gland. 3. To describe microscopic anatomy of the adrenal glands, thyroid and parathyroid glands as peripheral endocrine glands.
General provisions. 1. Endocrine system in collaboration with the nervous system, orchestrates homeostasis by influencing, coordinating, and integrating the physiological functions of the body. 2. Whereas the nervous system responds rapidly with a response of short duration, the endocrine system responds slowly, and the response is of longer duration. 3. Endocrine glands are responsible for the synthesis and secretion of chemical messengers known as hormones which are disseminated throughout the body by bloodstream where they act on specific target organs. Therefore endocrine glands possess an extensive vascular supply that is particularly rich in fenestrated capillaries. They have no excretory ducts as they discharge their product directly in blood. 4. Endocrine glands function by a regulatory system known as negative feedback in which production of a hormone affects a target organ to initiate a response that eventually reduces secretion of that hormone. 5. The endocrine system consists of several glands, composed of islands of secretory cells of epithelial origin, as well as of isolated groups of cells within certain organs, and individual cells scattered among parenchymal cells of the body.
Classification of the Endocrine System 1.Endocrine glands (pituitary, epiphysis, thyroid gland, parathyroid glands, adrenal glands). 2. Mixed glands (testes, ovaries, pancreas). 3. Paracrine system (APUD). Endocrine glands: 1. Central (pituitary hypothalamo-hypophyseal system; pineal gland epithalamo-epiphyseal system). 2. Peripheral (thyroid, parathyroid and adrenal glands, sex glands, pancreas). Peripheral endocrine glands: 1.Pituitary-dependent (thyroid gland, adrenal cortex, sex glands). 2.Pituitary independent (adrenal medulla, parathyroid glands, pancreas).
The hypophysis is a master endocrine gland connected to the hypothalamus at the base of the brain, with which is has important anatomic and functional relationship and formes hypothalamo-hypophyseal system providing the highest level of control of the endocrine functions. Similar relations exist between pineal gland and epithalamus forming epithalamoepiphyseal system. Other endocrine glands (thyroid, parathyroid, adrenal glands) are considered to be peripheral endocrine glands (purely endocrine ones). Pancreas, ovaries, testes combine functions of the endocrine and exocrine glands.
cavity of the 3rd ventricle optic chiasm pars tuberalis diaphragm sella mammil body median eminence pituitary stalk
post. pituitary
dura mater
anterior pituitary
neural lobe
sphenoid bone sella turcica pituitary fossa fibrocollagenous setum with cysts pars intermedia
The pituitary or hypophysis is divided into adenohypophysis and neurohypophysis having different embryonic origin. Adenohypophysis includes pars distalis (or pars anterior), pars tuberalis and pars intermedia. Neurohypophysis is formed by the posterior lobe of the gland.
Scheme of pituitary
The pituitary is suspended from the hypothalamus (H) by the infundibulum which is composed of ther neural portion (infundibular stem, IS) and the surrounding pars tuberalis (PT). The 3rd ventricle of the brain is continuous with the infundibular recess (IR). Pars anterior (PA) is the largest portion of the pituitary which is glandular and secretes numerous hormones. Pars nervosa (PN) does not manufacture hormones but stores and releases them. Pars intermedia (PI) is located between pars anterior and pars nervosa, it frequently presents intraglandular cleft (colloid-filled cyst) which is a remnant of Rathkes pouch.
Endocrine cells (E) of the adenohypophysi s are arranged in groups and surrounded by capillaries (C). The capillaries are wide, endothelially lined vessels known as sinusoids.
Lobus anterior (or pars distalis) comprises 80% of the pituitary, while pars intermedia in humans is less developed. Pars distalis is composed of large cords of cells that branch and anastomose with each other. Traditionally cells of the anterior lobe of the pituitary have been classified into three types: acidophils (A), (cytoplasm staining by acidic dyes), basophils (B) (cytoplasm staining by basic dyes and PAS-method) and chromophobes (CO) which do not stain.
The chromophobes do not take up the stain well and only their nuclei are demonstrable. They make about 50% of cells of pars distalis. These cells are small, therefore chromophobes are easily recognizable since their nuclei appear to be clumped together. They represent either nonspecific stem cells or partially degranulated chromophils.
Adenohypophysi s, PAS-Orage G.
On the picture acidophils (A) are stained bright, basophils (B) are stained dark while chromophobes (C) are not stained.
It is now customary to classify cells according to their hormone content which is demonstrable by modern immunohistochemocal methods of staing using antibodies to each hormone type. It was shown that acidophils are cells secreteing growth hormone and prolactine (i.e. somatotrophs and lactotrophs), and basophils (PAS+) are gonadotrophs, thyrotrophs or corticotrophs. Basophils stain well with hematoxylin and PAS which detect glycosil groups, as luteinizing hormone (LH), follicle stimulating hormone (FSG) and thyrocyte stimulating hormone (TSH) are glycoproteins, and the ACTH precursor protein is glycosylated.
Most of the chromophil cells in the pituitary (40%) are acydophils, and among them the majority are somatotrophs (arrows). Besides the granules, there are mant parallel cysterns of the RER in the cytoplasm. In the malignant cells thick bundles of the intermediate filaments may be discovered. Most of the granules measure 350-450 nm in diameter, though the range is between 300 and 600 nm.
Lactotrophs make up to 25% of the anterior pituitary. While some are rounded and polygonal (arrows), most are compressed by adjacent cells into narrow angular profiles). They increase in size and number during pregnancy and lactation. Ultrastructurally they have a prominent Golgi compared to all other anterior pituitary cells and their granules measure 200-350 nm in diameter. Interesingly, exocytosis may be seen at their lateral borders (misplaced exocytosis) as well as in the usual site adjacent to capillary basement membrane. This feature can be used in diagnostic assessments as it is limited to lactotrophderived tumors.
Constituting around 10% of anterior pituitary cells, gonadotrophs (arrow) are scattered as single cells or small groups throughout the gland as seen in this section stained for the beta-subunit of FSG by immunoperoxidease technique. Both FSH and LH may be evident within the same cell. Ultrastructurally the granules are 150-400 njm in diameter. Following ablation of the ovaries or testes, gonadotrophs develop extensive cytoplasmic vacuolation. This is due to dilation of the endoplasmatic reticulum by stored product and caused by the loss of feedback inhibition by gonadal steroids. Such cells, large rounded and vacuolated on light microscopy, are called castration cells.
It is also possible to distinguish cells of the anterior pituitary by elecron microscopy. The electron microphotograph reveals the presence of the dence core granules in the cytoplasms of adonocytes. Chromophobes fail to stain because they contain very few granules, and may be lactotrophs, somatotrophs, gonadotrophs, thyrotrophs or corticotrophs by nature.
Posterior pituitary is composed of axons which originate from cells in the hypothalamus and possess numerous neurosecretory granules containing either oxytocin or vasopressin together with a carrier protein termed neurophysin, and ATP. Where axons are adjacent to capillaries they form fusiform swellings filled with neurosecretory granules (Hering bodies). The posterior pituitary also contains specialized stellate-shaped glial cells called pituicytes. In the micrograph the axons are seen a pale fibrillary background in which the nuclei of pituicytes (P) and small capillary vessels are present.
Hypothalamic neurons secrete releasing/inhibiting factors in response to chemoreceptive and neural inputs. These hormones diffuse into capillaries at the median eminence and are carried to the anterior pituitary in the portal vessels. Astrocyte foot processes surrounding the cappilaries form part of their diffusion barrier.
capillary
neural synapse hypothalamic neuron releasing/ Inhibiting factor capillary at median eminence portal vessel basement membrane endothelial cell
astrocyte
astrocyte foot process
Summary of Histology of Pituitary and Hypophysis Loca- Gene-ralSpe-cific HorTarget Nature Gra- Staincell type cell type mone tion tissue/or of hor- nule ing
Func-tions
gan
mone
size
espepro-tein 300- Orange stimulates growth, cially 400 G promotes muscle nm protein and bone
prolactine
breast
mammary develop-ment
Target Nature Gra- Stain- Func-tions tissue/or of hor- nule ing gan mone size
stimulates develop-ment of follicles in the ovary & semini-ferous tubules in the testes
pars basoph gona-do- follicle- ovary & glyco- 150- PAS dista- il trophs stimu- testis pro-tein 200 lis of lating nm follithe horculopituitrophs mone tary
luteiovary Glyco- 150- PAS nizing (corpus pro-tein 200 hormon luteum) nm e
stimulates corpus luteum develop-ment & progesteron secretion: necessary for ovula-tion and estrogen secretion
Tar-get Nature Gra- Stain- Funcorgan of hor- nule ing tions mone size glyco- 150- PAS & pro-tein 200 aldenm hydestimulates Leidig fuchsin cells to PAS produce testosterone
stimulates synthesis of adrenocortical steroid hormones controls thyroxine production & release
basophil
corticotroph
adrenocorticotropin (ACTH)
basophil
Location
Hormone
Tar-get Natu-reGra- Stain- Func-tions organ of hor- nule ing mone size 200- PAS 300 nm stimulates melano-cyte expansion
storage and release of neurohormones of hypothalamus: vasopressin, oxytocin
melanotroph APUD
melano- skin of polycyte sti- lower pepmulating animals tide hormone (MSH)
none
hypo- neuro- neurons oxy-tocin smooth polymuscle, pepthalam secre- in paraventritory especi- tide us
neurons cular nuclei ally uterus
hypo- neuro- neu-rons vasopr renal poly100- Gomori increases water thalam secre- in supra- es-sin collect- pep-tide 300n absorption of tory us optical- (anti- ing m renal neunuclei diure- tubules, collecting rons tic hor- arterio-les tubules, moneconstricts ADH arterioles to
incease pressure neurosecretory neurons
neu-rons six re- pars leasing distalis in tuberal factors nuclei (RF); pars two known distalis inhibiting factors
pep-tide -
pep-tide
causes release of the anterior pituitary hormones; inhibits release of the anterior pituitary hormones
eye
nervus opticus
n.suprachiasmaticus
central sympathetic pathways
Diagram shows the location of the pineal gland. Output of pineal melatonin is modulated by light through nervous pathways which input as sympathetic innervation to the gland. It is also thought to influence gonadal activity (suppression). The parenchyma is composed of pinealocytes and interstitial cells. Pinealocytes are resposible for secretion of serotonin and melatonin, while the interstisial cells are believed to astroglia-like cells.
Pineal Gland
2) it is the only endocrine gland that depends on the external environment for raw materials of its hormones, 3) it possesses one of the richest blood flow compared to adrenal and other glands,
4) thyroid hormones are the only among amino-acid-derived hormones which being lipid-soluble, diffuse through the cell membrane and binds to intracellular hormone receptor proteins in the target cells (other amino acid-derived hormones receptors are present in the cell membrane of the target cells).
I. General Morphology 1. The thyroid gland consists of right and left lobes connected across the middle line by a narrow portion, the isthmus (and sometime pyramidal lobe). 2. Its weight is somewhat variable, but is usually about 30 grams. 3. It is slightly heavier in the female, in whom it becomes enlarged during menstruation and pregnancy. 4. Parenchyma of thyroid gland: follicles + interfollicular clusters of calcitoninocytes.
100 m
Stroma: the inner, true, connective tissue (CT) capsule sends in septa to partially enclose lobules separated by a loose CT, with many blood vessels. Follicles are the structural units of the thyroid gland. Note variations in shape (rounded or tubular) and size (0.05 to 0.5 mm in diameter). Close packing with a thin reticular network between adjacent follicles.
follicle
colloid
Lined by basophilic cuboidal follicular cells, varying in height from squamous to low columnar as a simple epithelium on a basal lamina, outside which is an extensive plexus of blood capillaries, and reticular fibres and fibroblasts. Follicular cells are polarized with respect to the follicle lumen. Nucleus is placed centrally or basally. Colloid is found in the lumen of follicles. It is variably acidophil or basophil, and often shrunken and showing knife chatters.
1. In man they vary markedly between 0.02 and 0.9 mm in diameter. 2. Larger follicles filled with colloid have a squamous or cuboidal epithelium. 3. Glands with follicles that have predominantly squamous epithelial cells are considered to be hypoactive. 4. When the gland is stimulated to synthesize thyroid hormone, the follicular epithelial cells become columnar and the amount of colloid is reduced. 5. Each follicle can store several weeks supply of hormone within colloid. 6. A gland has several million follicles. 7. Chemical composition of colloid is a glycoprotein-iodine complex (thyroglobulin). The follicles release about 100 mg of hormone daily. Of the several iodinated compounds found in the gland the 3, 5, 3-triiodothyronine is hormonally the most active.
Thyroid follicles:
In A, the colloid in the lumen of the follicle is not stained. In B, the colloid is specifically stained red with the periodic acidSchiff method because of the chemical composition of colloid, which is a glyco-protein-iodine complex (thyroglobulin).
Thyroid Physiology:
Follicular cells: (a) Are stimulated by pituitary thyrotrophic hormone (TSH) to produce and release two iodinated amino-acid hormones tetraiodothyronine (thyroxine/T4) and 3,5,3-triiodoL-thyronine(T3), (b) which are stored in the colloid, as component amino acids of the glycoprotein - thyroglobulin. (c) The hormones accelerate general and specific metabolic processes of the body.
(d) Electron radioautography has shown the sites in the sequence of hormone production by the follicular cells: cells i. Iodide concentration - basal part of the follicular cell. ii. iii. iv. v. vi. Iodide oxidation - throughout the cell. (ii) Synthesis of thyroglobulin - basal cell, granular ER, Golgi body, by vesicle to the lumen. In the luminal thyroglobulin, tyrosine residues are iodinated, then pairs condense. Cellular retrieval of thyroglobulin from colloid storage cell's apical region by endocytosis. Transport to lysosomes, where cathepsins degrade the large modified molecule.
vii. Release of freed iodothyronines - out of the base of the cells into the blood. viii. Binding to intracellular proteins after entering cytoplasm and slow use over a period of several days to weeks (both T3 and T4 bind to nuclear thyroid hormone receptor proteins, but T3 binds with a much greater affinity than does T4, which accounts for the greater biological activity of T3).
Diagram of the synthesis and iodination of thyroglobulin (A) and release of thyroid hormone (B).
2) T3 and T4: stimulate transcription of many genes that encode various types of proteins, resulting in a generalized increase in cellular metabolism that may be as great as twice resting rate; a) stimulate carbohydrate metabolism, b) decrease synthesis of cholesterol, phospholipids, and triglycerides but increase synthesis of fatty acids and the uptake of various vitamins, T3 and T4 also increase the growth rate in the young, facilitate mental processes, and stimulate endocrine gland activity.
c)
CLINICAL CORRELATES:
Increased thyroid hormone production: a) decreases body weight, b) increases heart rate, c) increases metabolism, muscle function, and appetite. respiration,
papillary infoldings
In thyroxic hyperplasia a number of follicular cells increases, papillary folds of acinar epithelium develop. In addition each epithelial cell is large columnar and the edges of colloid are scalloped, indicating active removal of stored colloid for processing into thyroxine.
CLINICAL CORRELATIONS: Overactivity of the thyroid (hyperthyroidism) may be due to a number of factors. In Graves disease, the thyroid is overactive even with low levels of THS, due to an immunologic disturbance in which an immunoglobulin has an effect similar to that of TSH (autoimmune IgG antibodies bind to TSH receptors which stimulate thyroid follicular cells).
1a) a dwarf child who is mentally retarded (cretinism). 2a) slow heart rate, muscular weakness, and gastrointestinal disturbances. Thyroid hormone given to infants at an early stage of cretinism can alleviate the symptoms.
b) in adults:
1b) mental slowing, 2b) cold intolerance, 3b) reflex changes, 4b) skin changes 5b) fatigue, sleeping for up to 16 hours per day, 6b) muscular sluggishness, 7b) slowed heart rate, decreased cardiac output and blood volume 8b) failure of body functions, 9b) constipation, 10b) loss of hair growth.
Patients with severe hypothyroidism may characterized by bagginess under the eyes nonpitting edema of the skin, infiltration of proteoglycans into the extracellular matix. develop myxedema, which is and swollen face that is due to excess glycosaminoglycans, and
Histophysiology of C-cells:
(a) they are APUD cells of neural crest origin, (b) and produce the polypeptide calcitonin for the reduction of high plasma Ca2+ and phosphate levels by inhibiting bone resorption by osteoclasts and decreasing calcium and phosphate reabsorbtion by renal tubules. It may increase the rate of osteoid mineralization. (c) although diffuse, in sum they form a gland antagonistic to the action of the parathyroids. (d) the secretion of calcitonin results from elevation of blood calcium concentration above normal levels.
Parafollicular cells are located between follicular cells or in the interstitial connective tissue.
A
Thyroid follicles
B
Parafollicular cells Interstitial aggregation of parafollicular cells
C
A 100 m B & C 50 m
the true capsule of the thyroid, the small parathyroid glands (4 to 5 mm in diameter) and are usually found on the posterior surface of the thyroid gland.
O C Stroma: Each of the four (may range from 2 to 12) rounded or ovoid bodies has a fine connective tissue capsule and delicate, incomplete septa which divide the gland in lobules. . These septa carry vessels, nerves and many fat cells. Parenchyma: supported on fine reticular fibres are many fenestrated blood capillaries and sheets and cords or plates of chief cells (small, 7-10 m diameter; some dark, some light: contain glycogen, lipofuscin pigment, and argyrophil secretory granules; form occasional small follicles.) and oxyphil cells (larger, acidophilic, and often occur in clumps; no secretory granules). The most abundant type is the chief (or principal) cell, which is functionally important.
Chief cells: with prominent nucleus, round and centrally located, and cytoplasm that stains variably and may be light or dark depending upon its secretory activity. The second type, oxyphilic (acidophilic or eosinophilic) cells, occurs in fewer numbers in small clumps or nests among chief cells. Larger than chief cells. Oxyphilic cells usually arise after puberty and increase in number beyond the age of 40 but their specific function is unknown. May be derived from chief cells. Oxyphil cells: occurs in small clumps and in fewer numbers. These cells usually have small densely staining heterochromatin and an oxyphilic cytoplasm whose perimeter is usually well defined.
3.Functions
(a) Secretory granules of chief cells are the polypeptide hormone, parathormone/PTH, which is important in calcium and phosphate metabolism acting mainly on bone and the kidney: 1a) it is released in response to low blood Ca2+, 2a) acts on osteoclasts and macrophages to increase bone resorption, 3a) it also removes calcium phosphate directly from bone matrix, and, via intermediary factors, from osteoblasts;. (b) in the kidney: 1b) PTH: promotes the tubular reabsorption of calcium 2b) inhibits the renal tubular reabsorption of phosphate - a phosphaturic action; (c) promotes conversion of 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D (this metabolite increases calcium absorbtion by the gut);
(d) unlike most other endocrine glands, no specific pituitary trophic hormone is involved in its control.
Clinical Correlates:
Parathyroid glands are essential for life whereas calcitonin of the thyroid appears to provide a complementary mechanism for fine adjustment of blood calcium level and is not essential for life. In the absence of parathyroid hormone, there is a pronounced decrease in blood calcium resulting in tetany, abnormal twitching, the intense, involuntary spasm of skeletal muscle. caused by changes in excitability at the neuromuscular junction, and death. Dietary addition of calcium and especially administration of parathyroid hormone relieves the abnormal spasms, preventing death of the organism. Abnormal levels of calcium may result in abnormal deposition of calcium in the kidneys and muscle. Abnormally increased blood levels of calcium occur at the expense of bone, which may fracture as a result.
Adrenal Gland
Cortex: Zona glomerulosa (narrow subcapsular zone of cortex) secretes mineralocorticoids, mainly aldosterone. Zona fasciculata (broad, yellow mid-zone of cortex) secretes glucocorticoids, mainly cortisol and corticosterone. Zona reticularis (narrow inner zone of cortex) secretes mainly androgenic steroids.
medulla
cortex
z.reticularis
z.fasciculata Adrenal medulla (central, enclosed by cortex, brown) is neuroendocrine and secretes epinephrine and norepinephrine (noradrenaline).
z.glomerulosa
capsule
Zona fasciculata contains cells arranged in vertical columns, which are usually 2-3 cells wide, the columns being separated by capillaries (Cap).
The inner zona reticularis produces androgenic steroids and some glucocorticoids, but normally only in small amounts. The inner zone of adrenal cortex is thinner than the zona fasciculata, but thicker than the zona glomerulosa. It is composed of cells with eosinophylic cytoplasm arranged in an anastomosing network of clumps and columns with a capillary network closely apposed to the cell membranes. A characteristic feature of this layer when stained with H & E is the present of brown pigment (lipofuscin). To the naked eye the layer appears pale brown, whereas the zona fasciculata is bright yellow.
Because of their high catecholamine content, adrenal medullary cells develop an intensive brown color when exposed to air or to a strong oxidizing agent, such as potassium dichromate, due to the formation of brown pigment when the amines are oxydized. This is the basis of their antiquated name chromaffin cells. Adrenal medullary cells (E- and N-cells) show their large nuclei and finely granular cytoplasm.
Large dense-core granules corresponding to norepinephrine (N) and epinephrine (E) granules.