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Chapter 18 The 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 con...
Chapter 18 The 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. The anterior pituitary secretes thyroid-stimulating hormone (TSH, thyrotropin), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), folliclestimulating hormone (FSH), prolactin, and growth hormone (see Figure 17–9), 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. Of the listed hormones, prolactin acts on the breast. The remaining five are, at least in part, tropichormones; 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. 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. Nevertheless, the intermediate lobe, as well as the anterior pituitary, contains hormonally active of the proopiomelanocortin (POMC) molecule that regulate skin pigmentation, among other functions (see below). 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. 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 18–1. Some cells may contain two or more hormones. 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 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; a second, hGH-V, codes for the variant form of growth hormone; two code for human chorionic somatomammotropin (hCS) and the fifth is probably an hCS pseudogene. 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. 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 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 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 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. 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 (Figure 18–3). Dimerization is essential for receptor activation. Growth hormone has widespread effects in the body (see below), 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 (Figure 18–3). 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 Effects on Growth In young animals in which the epiphyses have not yet fused to the long bones, 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. 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 Effect 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. 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 4-hydroxyproline is increased during this growth, reflective of the ability of growth hormone to stimulate the synthesis of soluble collagen 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 anti-insulin effect in muscle. Growth hormone is also ketogenic and increases circulating free fatty acid (FFA) levels. 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 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. 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. The hormone relaxin is also a member of this family. Humans have two related relaxin isoforms, and both resemble IGF-II 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. Secretion of IGF-I is independent of growth hormone before birth but is stimulated by growth hormone after birth, and it has pronounced growthstimulating 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. 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
