Endocrine System | Pituitary Gland PDF

Physiology Endocrine System Chapter 18 |Pituitary Gland Endocrine System | Pituitary Gland Contents : Introduction 3 Cell types in the anterior pituitary 11 Growth Hormone 14 Biosynthesis & Chemistry 15 Plasma Levels, Binding, & Metabolism 18 Growth Hormone Receptors 20 Effects Of Growth hormones 24...

Physiology Endocrine System Chapter 18 |Pituitary Gland Endocrine System | Pituitary Gland Contents : Introduction 3 Cell types in the anterior pituitary 11 Growth Hormone 14 Biosynthesis & Chemistry 15 Plasma Levels, Binding, & Metabolism 18 Growth Hormone Receptors 20 Effects Of Growth hormones 24 Gigantism & Acromegaly 31 Somatomedins 40 Chapter Summary 48 Endocrine System | Pituitary Gland Introduction : The pituitary gland, or hypophysis, lies in a pocket of the sphenoid bone at the base of the brain. It is a coordinating center for control of many downstream endocrine glands, some of which are discussed in subsequent chapters. In many ways, it can be considered to consist of at least two (and in some species, three) separate endocrine organs that contain a plethora of hormonally active substances. Endocrine System | Pituitary Gland The anterior pituitary secretes thyroid-stimulating hormone (TSH, thyrotropin), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, and growth hormone , and receives almost all of its blood supply from the portal hypophysial vessels that pass initially through the median eminence, a structure immediately below the hypothalamus. This vascular arrangement positions the cells of the anterior pituitary to respond efficiently to regulatory factors released from the hypothalamus. Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland Of the listed hormones, prolactin acts on the breast. The remaining five are, at least in part, tropic hormones; that is, they stimulate secretion of hormonally active substances by other endocrine glands or, in the case of growth hormone, the liver and other tissues. The tropic hormones for some endocrine glands are discussed in the chapter on that gland: TSH ; and ACTH. However, the gonadotropins FSH and LH, along with prolactin. Endocrine System | Pituitary Gland The posterior pituitary in mammals consists predominantly of nerves that have their cell bodies in the hypothalamus, and stores oxytocin and vasopressin in the termini of these neurons, to be released into the bloodstream. The secretion of these hormones, as well as a discussion of the overall role of the hypothalamus and median eminence in regulating both the anterior and posterior pituitary. In some species, there is also a well-developed intermediate lobe of the pituitary, whereas in humans it is rudimentary. Endocrine System | Pituitary Gland Nevertheless, the intermediate lobe, as well as the anterior pituitary, contains hormonally active derivatives of the proopiomelanocortin (POMC) molecule that regulate skin pigmentation, among other functions. To avoid redundancy, this chapter will focus predominantly on growth hormone and its role in growth and facilitating the activity of other hormones, along with a number of general considerations about the pituitary. The melanocyte-stimulating hormones (MSHs) of the intermediate lobe of the pituitary, α-MSH and β-MSH, will also be touched upon. Endocrine System | Pituitary Gland Cell types in the anterior pituitary Five types of secretory cells have been identified in the anterior pituitary by immunocytochemistry and electron microscopy. The cell types are the somatotropes, which secrete growth hormone; the lactotropes (also called mammotropes), which secrete prolactin; the corticotropes, which secrete ACTH; the thyrotropes, which secrete TSH; and the gonadotropes, which secrete FSH and LH. The characteristics of these cells are summarized in Table. Some cells may contain two or more hormones. Endocrine System | Pituitary Gland TABLE : Hormone-secreting cells of the human anterior pituitary gland : Cell Type Hormones Secreted Percentage of Total Secretory Cells Somatotrope Growth hormone 50 Lactotrope Prolactin 10-30 Corticotrope ACTH 10 Thyrotrope TSH 5 Gonadotrope FSH, LH 20 Endocrine System | Pituitary Gland It is also notable that the three pituitary glycoprotein hormones, FSH, LH, and TSH human chorionic gonadotropin (hCG) has α and β subunits Growth Hormone Endocrine System | Pituitary Gland Growth Hormone : Biosynthesis & Chemistry The long arm of human chromosome 17 contains the growth hormone-hCS cluster that contains five genes: One, hGH-N, codes for the most abundant (“normal”) form of growth hormone. Second, hGH-V, codes for the variant form of growth hormone. Two code for human chorionic somatomammotropin (hCS). Fifth is probably an hCS pseudogene. Endocrine System | Pituitary Gland Growth hormone that is secreted into the circulation by the pituitary gland consists of a complex mixture of hGH-N, peptides derived from this molecule with varying degrees of posttranslational modifications, such as glycosylation, and a splice variant of hGH-N that lacks amino acids 32–46. The physiologic significance of this complex array of hormones has yet to be fully understood, particularly since their structural similarities make it difficult to assay for each species separately. Endocrine System | Pituitary Gland Nevertheless, there is emerging evidence that, while the various peptides share a broad range of functions, they may occasionally exert actions in opposition to one another. hGH-V and hCS, on the other hand, are primarily products of the placenta, and as a consequence are only found in appreciable quantities in the circulation during pregnancy. Endocrine System | Pituitary Gland Plasma Levels, Binding, & Metabolism: A portion of circulating growth hormone is bound to a plasma protein that is a large fragment of the extracellular domain of the growth hormone receptor. It appears to be produced by cleavage of receptors in humans, and its concentration is an index of the number of growth hormone receptors in the tissues. Approximately 50% of the circulating pool of growth hormone activity is in the bound form, providing a reservoir of the hormone to compensate for the wide fluctuations that occur in secretion. Endocrine System | Pituitary Gland The basal plasma growth hormone level measured by radioimmunoassay in adult humans is normally less than 3 ng/mL. This represents both the protein-bound and free forms. Growth hormone is metabolized rapidly, at least in part in the liver. The half-life of circulating growth hormone in humans is 6–20 min, and the daily growth hormone output has been calculated to be 0.2–1.0 mg/d in adults. Endocrine System | Pituitary Gland Growth Hormone Receptors : The growth hormone receptor is a 620-amino-acid protein with a large extracellular portion, a transmembrane domain, and a large cytoplasmic portion. It is a member of the cytokine receptor superfamily which is discussed in Chapter 3. Endocrine System | Pituitary Gland Growth hormone has two domains that can bind to its receptor, and when it binds to one receptor, the second binding site attracts another, producing a homodimer. Dimerization is essential for receptor activation. Growth hormone has widespread effects in the body, so even though it is not yet possible precisely to correlate intracellular and whole body effects, it is not surprising that, like insulin, growth hormone activates many different intracellular signaling cascades. Endocrine System | Pituitary Gland Of particular note is its activation of the JAK2–STAT pathway. JAK2 is a member of the Janus family of cytoplasmic tyrosine kinases. STATs (for signal transducers and activators of transcription) are a family of cytoplasmic transcription factors that, upon phosphorylation by JAK kinases, migrate to the nucleus where they activate various genes. JAK–STAT pathways are known also to mediate the effects of prolactin and various other growth factors. Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland Effects On Growth : In young animals in which the epiphyses have not yet fused to the long bone, growth is inhibited by hypophysectomy and stimulated by growth hormone. Chondrogenesis is accelerated, and as the cartilaginous epiphysial plates widen, they lay down more bone matrix at the ends of long bones. In this way, stature is increased. Prolonged treatment of animals with growth hormone leads to gigantism. Endocrine System | Pituitary Gland When the epiphyses are closed, linear growth is no longer possible. In this case, an overabundance of growth hormone produces the pattern of bone and soft tissue deformities known in humans as acromegaly. The sizes of most of the viscera are increased. The protein content of the body is increased, and the fat content is decreased. Endocrine System | Pituitary Gland Effects On Protein & Electrolyte Homeostasis : Growth hormone is a protein anabolic hormone and produces a positive nitrogen and phosphorus balance, a rise in plasma phosphorus, and a fall in blood urea nitrogen and amino acid levels. In adults with growth hormone deficiency, recombinant human growth hormone produces an increase in lean body mass and a decrease in body fat, along with an increase in metabolic rate and a fall in plasma cholesterol. Endocrine System | Pituitary Gland Gastrointestinal absorption of Ca2+ is increased. Na+ and K+ excretion is reduced by an action independent of the adrenal glands, probably because these electrolytes are diverted from the kidneys to the growing tissues. On the other hand, excretion of the amino acid 4hydroxyproline is increased during this growth, reflective of the ability of growth hormone to stimulate the synthesis of soluble collagen. Endocrine System | Pituitary Gland Effects On Carbohydrate & Fat Metabolism: The actions of growth hormone on carbohydrate metabolism are discussed in Chapter 24. At least some forms of growth hormone are diabetogenic because they increase hepatic glucose output and exert an antiinsulin effect in muscle. Growth hormone is also ketogenic and increases circulating free fatty acid (FFA) levels. Endocrine System | Pituitary Gland The increase in plasma FFA, which takes several hours to develop, provides a ready source of energy for the tissues during hypoglycemia, fasting, and stressful stimuli. Growth hormone does not stimulate β cells of the pancreas directly, but it increases the ability of the pancreas to respond to insulinogenic stimuli such as arginine and glucose. This is an additional way growth hormone promotes growth, since insulin has a protein anabolic effect. Gigantism & Acromegaly Endocrine System | Pituitary Gland Gigantism & Acromegaly: Tumors of the somatotropes of the anterior pituitary (pituitary adenomas) secrete large amounts of growth hormone, leading to gigantism in children and to acromegaly in adults. If the tumor arises before puberty, the individual may grow to an extraordinary height. Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland After linear growth is no longer possible, on the other hand, the characteristic features of acromegaly arise, including greatly enlarged hands and feet, vertebral changes attributable to osteoarthritis, soft tissue swelling, hirsutism, and protrusion of the brow and jaw. Abnormal growth of internal organs may eventually impair their function such that the condition, which has an insidious onset, can prove fatal if left untreated. Hypersecretion of growth hormone is accompanied by hypersecretion of prolactin in 20–40% of patients with acromegaly. Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland About 25% of patients have abnormal glucose tolerance tests, and 4% develop lactation in the absence of pregnancy. Acromegaly can be caused by extra pituitary as well as intrapituitary growth hormone–secreting tumors and by hypothalamic tumors that secrete GHRH, but the latter are rare. Endocrine System | Pituitary Gland Therapeutic Highlights The mainstay of therapy for acromegaly remains the use of somatostatin analogues that inhibit the secretion of growth hormone. A growth hormone receptor antagonist has become available and has been found to reduce plasma IGF-I and produce clinical improvement in cases of acromegaly that do not respond to other treatments. Endocrine System | Pituitary Gland Surgical removal of the pituitary tumor is also helpful in both acromegaly and gigantism, but sometimes challenging to perform due to the tumor’s often invasive nature. In any case, adjuvant pharmacologic therapy must often be continued after surgery to control ongoing symptoms. Somatomedins Endocrine System | Pituitary Gland Somatomedins : The effects of growth hormone on growth, cartilage, and protein metabolism depend on an interaction between growth hormone and somatomedins, which are polypeptide growth factors secreted by the liver and other tissues. The first of these factors isolated was called sulfation factor because it stimulated the incorporation of sulfate into cartilage. However, it also stimulated collagen formation, and its name was changed to somatomedin. Endocrine System | Pituitary Gland It then became clear that there are a variety of different somatomedins and that they are members of an increasingly large family of growth factors that affect many different tissues and organs. The principal (and in humans probably the only) circulating somatomedins are insulin-like growth factor I (IGF-I, somatomedin C) and IGF-II. These factors are closely related to insulin, except that their C chains are not separated and they have an extension of the A chain called the D domain. Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland The hormone relaxin is also a member of this family. Humans have two related relaxin isoforms, and both resemble IGF-II. In humans a variant form of IGF-I lacking three amino terminal amino acid residues has been found in the brain, and there are several variant forms of human IGF-II. The mRNAs for IGF-I and IGF-II are found in the liver, other proteins to intracellular organelles. Endocrine System | Pituitary Gland Secretion of IGF-I is independent of growth hormone before birth but is stimulated by growth hormone after birth, and it has pronounced growth-stimulating activity. Its concentration in plasma rises during childhood and peaks at the time of puberty, then declines to low levels in old age. IGF-II is largely independent of growth hormone and plays a role in the growth of the fetus before birth. Endocrine System | Pituitary Gland Endocrine System | Pituitary Gland In human fetuses in which it is overexpressed, several organs, especially the tongue, other muscles, kidneys, heart, and liver, develop out of proportion to the rest of the body. In adults, the gene for IGF-II is expressed only in the choroid plexus and meninges. Chapter Summary Endocrine System | Pituitary Gland Chapter Summary : The pituitary gland plays a critical role in regulating the function of downstream glands, and also exerts independent endocrine actions on a wide variety of peripheral organs and tissues. It consists of two functional sections in humans: the anterior pituitary, which secretes mainly tropic hormones; and the posterior pituitary, which contains nerve endings that release oxytocin and vasopressin. The intermediate lobe is prominent in lower vertebrates but not in humans or other mammals. Endocrine System | Pituitary Gland Corticotropes of the anterior lobe synthesize proopiomelanocortin, which is the precursor of ACTH, endorphins, and melanotropins. The latter have a critical role in the control of skin coloration in fish, amphibians, and reptiles, whereas ACTH is a primary regulator of skin pigmentation in mammals. Growth hormone is synthesized by somatotropes. It is secreted in an episodic manner in response to hypothalamic factors, and secretion is subject to feedback inhibition. A portion of the circulating pool is protein-bound. Endocrine System | Pituitary Gland Growth hormone activates growth and influences protein, carbohydrate, and fat metabolism to react to stressful conditions. Many, but not all, of the peripheral actions of growth hormone can be attributed to its ability to stimulate production of IGF-I. Growth reflects a complex interplay of growth hormone, IGF-I, and many other hormones as well as extrinsic influences and genetic factors. The consequences of overproduction or underproduction of such influences depends on whether this occurs before or after puberty. Endocrine System | Pituitary Gland Deficiencies in components of the growth hormone pathway in childhood lead to dwarfism; overproduction results in gigantism, acromegaly, or both. The pituitary also supplies hormones that regulate reproductive tissues and lactation—follicle-stimulating hormone, luteinizing hormone, and prolactin. Prolactin, in particular, is regulated by many of the factors that also regulate growth hormone secretion, although specific regulators may have opposing effects.