ENDOCRINE SYSTEM II
PITUITARY GLAND & ENDOCRINE PANCREAS

Reading assignment: pages 644-653, 555-559, Histology, 4th ed.; by Ross, Kaye, and Pawlina.

1. PITUITARY GLAND
   
   The pituitary gland (also known as the hypophysis) is derived from an evagination of the stomodeum (Rathke’s pouch) that forms the adenohypophysis (anterior pituitary), and an evagination of the diencephalon that forms the neurohypophysis (posterior pituitary). These structures reside in the sella turcica of the sphenoid bone. The gland weighs approximately 600 mg and is about 10 mm long (anterior-posterior axis), 15 mm wide, and 6 mm in height.
   
   The neurohypophysis retains its connection with the brain via the infundibulum. The adenohypophysis loses its connection with the pharynx but consists of three regions: the pars distalis forms the bulk of the adenohypophysis; the pars tuberalis wraps around the infundibulum; and the pars intermedia (intermediate lobe) is a small, indistinct, portion of the gland that lays between the pars distalis and the neurohypophysis.
   
   
   1. Adenohypophysis:
      
      This tissue is loosely organized as cords of hormone secreting cells separated by large diameter capillaries lined with fenestrated endothelium. The cells of the adenohypophysis synthesize, store (as cytoplasmic granules surrounded by a membrane), and secrete hormones that regulate activity in many other tissues. These hormones are all small proteins or glycoproteins.
      
      
      1. Pars Distalis:
         This tissue forms most of the adenohypophysis. Based on tinctorial properties of the tissue following histochemical staining, the cells of the adenohypophysis have been segregated into three basic types; the basophils (10% of the cell population), acidophils (40%), and chromophobes (50%). Histochemical identification of the different cell types of the pituitary is not very precise. However, electron microscopy and immunolabeling have provided precise characterization of the different cell types based on the specific hormone produced by each cell.
         
         Note that the terms basophil and acidophil as used in reference to the adenohypophysis refer to the staining characteristics of the cytoplasmic granules, and not simply the general color of the cytoplasm. You may find chromophobes (which lack granules) with blue cytoplasm due to accumulating ribosomes, but that does not make it a basophil.
         
         Basophils - These include the gonadotroph cells that secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). Also included are the thyrotrophs that secrete thyroid stimulating hormone (TSH) and corticotrophs that secrete adrenocorticotropic hormone (ACTH). Basophils are not distributed evenly throughout the pars distalis.
         
         Acidophils - This group includes cells that secrete growth hormone (GH) or prolactin.
         
         Chromophobes - These cells lack granules (or have too few to see) and often appear relatively unstained, depending on their physiological state. It is now recognized that cells identified as chromophobes are actually degranulated forms of the secretory cells.
         
         Hormones of the adenohypophysis
         
         
         • Growth hormone (GH, somatotropin) - causes production of somatomedin (also known as insulin-like growth factor, or IGF), which induces growth of long bones. GH and IGF also produce other metabolic effects not specifically related to its bone growth inducing properties.
         
         
         • Prolactin - promotes mammary gland development, initiates and maintains milk production.
         
         
         • Adrenocorticotropic hormone (ACTH) - stimulates secretion of glucocorticoids and androgenic steroids from the adrenal cortex. ACTH is cleaved from a gene product called pro-opiomelanocortin (POMC). POMC also yields melanocyte stimulating hormone (MSH), lipotropin, and beta endorphin.
         
         
         • Follicle stimulating hormone (FSH) - stimulates follicle development in the ovary and spermatogenesis in the testis.
         
         
         • Luteinizing hormone (LH) - also known as interstitial cell stimulating hormone (ICSH) - controls maturation of ovarian follicles and formation of a corpus luteum, induces steroid formation by the follicle and corpus luteum. ICSH is necessary for the maintenance of, and androgen secretion by, the interstitial cells (Leydig cells) of the testis.
         
         
         • Thyrotropin (thyroid stimulating hormone, TSH) - stimulates growth of thyroid epithelial cells and release of thyroid hormones into the blood.
      
      
      2. The pars intermedia in humans is not a distinct zone. It may contain cells that surround small, colloid filled cysts that contain material of unknown composition. Some sources claim that the cysts are residual spaces formed from Rathke’s pouch, while others dispute this. In any case, cells of the pars intermedia can be found dispersed in adjacent areas of the neurohypophysis and pars distalis.
      
      
      3. The pars tuberalis extends around the stalk of the pituitary and contains gonadotroph cells.
      
      
      Folliculostellate cells form a loose network within the anterior pituitary. These star-shaped cells extend long cytoplasmic processes among the hormone secreting cells of the gland and form connections with other folliculostellate cells via gap junctions. Evidence suggests that these cells participate in regulating the secretions of hormone secreting cells.
   
   
   Regulation of adenohypophysis secretion
   
   Adenohypophysis secretion is regulated by hormones produced by the hypothalamus (a region of the brain located immediately superior to the pituitary gland) and by hormones produced in peripheral target glands.
   
   The hypothalamus in turn receives neural input from many other areas of the brain that monitor physiological functions. These interactions between the brain and pituitary comprise the “neuroendocrine” connection between the central nervous system and the endocrine system.Regulatory factors produced by the hypothalamus (small proteins called hypophysiotropic hormones) are carried to the adenohypophysis via the hypophyseal portal system. Capillaries draining the hypothalamus form small portal veins that deliver blood to the adenohypophysis (which has almost no direct arterial supply). These veins form another capillary bed in the adenohypophysis where hypophysiotropic hormones are delivered to the secretory cells. When stimulated, hormones released by cells of the adenohypophysis enter these capillaries which drain primarily into the cavernous sinus, then into the gene<br>ral circulation. Adenohypophysis secretion is down regulated by other hypothalamic factors or by feedback inhibition due to elevated concentrations of end products produced by target organs. Feedback inhibition reduces hormone secretion by acting on cells of the hypothalamus and/or the adenohypophysis.
   
   Hypophysiotropic hormones:
   
   

   Hormone	Action
   Growth hormone releasing hormone (GHRH)	stimulates GH secretion
   Somatostatin	inhibits secretion of GH
   Prolactin inhibiting factor (PIF, dopamine)	inhibits secretion of prolactin
   Corticotrophin releasing hormone (CRH)	stimulates secretion of ACTH
   Gonadotropin releasing hormone (GnRH)	stimulates secretion of LH and FSH
   Thyrotropin releasing hormone (TRH)	stimulates secretion of TSH and prolactin

   
   

   2. Neurohypophysis:
      
      The expanded portion is called the pars nervosa, which remains connected to the hypothalamus of the brain by the infundibulum (the stalk of the pituitary). The pars nervosa contains axons and nerve terminals from cell bodies located in the supraoptic and paraventricular nuclei of the hypothalamus. The hormones of the neurohypophysis are synthesized in these cell bodies. Therefore, the neurohypophysis is not a gland but a storage site for neurosecretions. The unmyelinated axons connecting these cell bodies to the pars nervosa comprise the infundibulum. Secretory granules are located in the axon all along its length. These neurons are unusual in that they terminate on blood vessels rather than on other nerve cells. Large accumulations of these secretory granules are called Herring bodies. Note that the word “nucleus” as used here refers to a specific cluster of cell bodies in the central nervous system, not the membrane enclosed packet of genetic material.
      
      The neurons terminating in the neurohypophysis synthesize either of two hormones; antidiuretic hormone (ADH, also called vasopressin), or oxytocin. Each hormone is comprised of 9 amino acids and each is bound to carrier proteins called neurophysins.
      
      Antidiuretic hormone (ADH) acts to increase the rate of water resorption in the distal convoluted tubules and collecting ducts of the kidney. It is secreted in response to elevated plasma osmolality or a decrease in blood volume. ADH can also induce contraction of vascular smooth muscle, thus elevating blood pressure.
      
      Oxytocin induces contraction of smooth muscle in the uterus and myoepithelial cells of the mammary gland. Oxytocin secretion occurs as a result of neural stimuli that reach the hypothalamus, causing a reflex response. In the breast the reflex is initiated by suckling. In the uterus the reflex is initiated by stretching the cervix and vagina.
      
      The pituicyte is the only cell type unique to the neurohypophysis. These cells resemble astrocyte glial cells, with processes that terminate on blood vessels. They have round to oval nuclei and pigment granules are present in the cytoplasm. Fibroblasts and mast cells are also present.
      
      Abnormalities of pituitary function often become clinically relevant as a result of excess (hyperpituitarism) or diminished (hypopituitarism) secretion of hormones. Hyperpituitarism may be caused by a functional (hormone secreting) tumor. These tumors are usually homogeneous in their microscopic appearance due to their derivation from a single cell type. Even nonfunctional pituitary tumors (lacking hormone secretion) may cause hormonal imbalances as a result of growth into, and destruction of, adjacent normal pituitary tissue. Tumor expansion in the sella turcica may also cause defects in vision due to its proximity to the optic chiasma.


2. PANCREAS
   
   Clusters of endocrine cells, known as the pancreatic islets (or islets of Langerhans), are scattered throughout the pancreas. The highly vascular islets vary in size from a few cells up to several hundred. These islets are most numerous in the pancreatic tail and represent about 1-2% of the volume of the organ.
   
   In H&E stained sections the islets are seen as pale clusters of cells infiltrated by capillaries. Islets are separated from the exocrine pancreatic tissue by a thin rim of connective tissue. Islets contain protein secretory cells that are not easily distinguished from each other by routine staining methods. The secretory granules of the different cells are morphologically different when examined by electron microscopy. The different cell types can be readily identified with light microscopy immunolabeling.
   
   Alpha cells secrete glucagon. Glucagon serves to elevate the concentration of blood glucose. Secretory granules possess a dense round core surrounded by a pale zone. These cells comprise about 20% of the islet secretory cell population.
   
   Beta cells synthesize insulin. Insulin acts by promoting cellular uptake of glucose, thus decreasing blood glucose concentrations. Secretory granules contain a dense polyhedral core. Failure of the beta cells to secrete sufficient insulin causes the complex disease known as diabetes mellitus. Beta cells make up around 75% of the islet cell population.
   
   Delta cells secrete somatostatin. Somatostatin in the islets may inhibit secretion of insulin and glucagon in adjacent cells. Granules in delta cells contain material of moderate density and are heterogeneous in size. These cells represent about 5% of the islet cells.
   
   F cells (or PP cells) secrete pancreatic polypeptide. These cells represent only a small portion of the islets. This hormone inhibits gallbladder contraction, pancreatic exocrine secretion, and gastric acid secretion. Granules in these cells are small in diameter with homogeneous contents.