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Somatomedins are also known as insulinlike growth factors (IGFs); the most important of these isIGF-1, which is produced by the liver and other tissues inresponse to growth hormone. IGF-1 binds to receptors ontarget tissues producing tyrosine kinase activation, similar tothe actions of insulin on its receptor, resulting in intracellulareffects.IGF-1 is produced by the liver and secreted into thebloodstream in response to growth hormone; it is alsoproduced directly at target tissues. Although plasma levels ofIGF-1 respond to growth hormone stimulation of the liver, itis believed that local production of IGF-1 at the target tissues,as opposed to circulating IGF-1, is probably more important inmediating the effects of growth hormone on those tissues.Both growth hormone and IGF-1 exert negative feedbackeffects on the hypothalamus and anterior pituitary; GHRHinhibits its own release.
Metabolites also affect growthhormone release directly or indirectly: Glucose and free fattyacids inhibit GHRH release, whereas amino acids stimulatepituitary release of growth hormone.GROWTH HORMONEGrowth hormone (also known as somatotropin) is a 191amino acid, single-chain polypeptide with structural similarities to prolactin and human chorionic somatotropin (a placental hormone with growth hormone–like effects).
Asimplied by its name, growth hormone is the primary hormonein the human growth process. It is secreted throughout life,in a pattern that consists of basal secretion upon which severaldaily pulses of secretion are superimposed. These pulses occurduring sleep and are especially pronounced and frequentduring the pubertal growth spurt; basal secretion rates arehighest in young children.
The growth spurt in boys typicallybegins at about 12 years of age, and growth in height is usuallyconcluded by about 16 or 17 years of age, although there issignificant variability between individuals in both parameters.The growth spurt in girls begins about a year earlier and isconcluded about 2 years earlier, again with considerablevariability.Regulation of Growth Hormone SecretionThe secretion of growth hormone by anterior pituitarysomatotrophs is regulated by two hypothalamic hormones(Fig.
26.8):Effects of Growth Hormone and IGF-1The primary roles of growth hormone and IGF-1 arestimulation of growth and development of the bodyduring childhood and adolescence and regulation of metabolism and body composition in adults (see Fig. 26.8). Thesegeneral effects reflect more specific actions mediatedby IGF-1:■■■■Stimulation of linear growth, through proliferativeeffects, amino acid uptake, and protein synthesis in boneand cartilage (in childhood and adolescence).Increase in muscle mass (anabolic effect), throughincreased amino acid uptake and protein synthesis inmuscle.Decreased adiposity by stimulation of lipolysis.Increase in organ size, associated with proliferation andprotein synthesis.The actions of IGF-1 on growth of muscle, bone, and otherorgans involve stimulation of RNA and DNA synthesis as wellits more direct effects on cellular amino acid uptake and synthesis of protein.General Principles of Endocrinology and Pituitary and Hypothalamic Hormones317AminoacidsGlucoseFFAHypothalamusSomatostatinGHRHPituitaryGHGHLiver andother tissuesSomatomedin(IGF)Increased linear growthIncreased organ sizeSomatomedin(IGF)Decreased adiposityIncreased leanbody massFigure 26.8 Growth Hormone Growth hormone release by the anterior pituitary is controlled byGHRH and somatostatin.
Growth hormone has an important role in growth and development of childrenand regulation of metabolism. Its effects are mediated by somatomedins produced by the liver or by specifictarget tissues. AA, amino acids; FFA, free fatty acids; GH, growth hormone; GHRH, growth hormone–releasing hormone; IGF, insulin-like growth factor.Recent studies have led to the discovery of several hormones involved in growth, appetite, and obesity.
Ghrelinis a 26 amino acid, acylated peptide hormone producedby the stomach as well as the arcuate nucleus of the hypothalamus. Its actions include stimulation of hunger and release ofgrowth hormone and may provide a link between food intakeand growth stimulation. Its effects on hunger oppose the actionsof leptin, a hormone produced by adipose tissue that causessatiety. Current research is focusing on the relationship of theseand other hormones to obesity.Growth hormone is often referred to as a diabetogenichormone because of its metabolic effects and opposition ofthe actions of insulin.
Growth hormone acts to:■■■Elevate blood glucose levels through inhibition ofglucose uptake by muscle and adipose tissue.Elevate plasma free fatty acids through its lipolyticaction in adipose tissue.Induce insulin resistance and elevate plasma insulinlevels.318Endocrine PhysiologyCLINICAL CORRELATEGrowth Hormone Excess and DeficiencyDeficiency of growth hormone in prepubertal children results inshort stature and may delay the onset of puberty.
Deficiency mayresult from a variety of causes, including primary failure to secretegrowth hormone, low GHRH production, pituitary or hypothalamic damage, and deficiency in IGF production. Affected children are treated with recombinant human growth hormonetherapy. Deficiency in growth hormone can also occur in adults,often as a result of a pituitary tumor. Such deficiency can havemultiple manifestations, including loss of muscle mass, weightgain, and psychosocial effects; human growth hormone therapy isbeneficial in some cases.The most common cause of excess growth hormone is a growthhormone–secreting adenoma.
These are slowly growing tumorsthat are usually diagnosed in midlife; surgery is the most commontreatment. Growth hormone excess in adulthood produces acromegaly, a condition characterized by thickening of the bones ofthe hands, feet, and jaw; protrusion of the jaw and brow; andenlargement of the tongue (macroglossia), as well as cardiovascular and renal complications, diabetes, and other effects. Prepubertal growth hormone excess is rare and causes pituitarygigantism.Acidophil adenomaAdenomaSphenoid sinusRelatively small, slow-growing adenoma, causingendocrine symptoms (acromegaly) with littlemechanical disturbanceInvasive (malignant) adenoma; extension intoright cavernous sinusLarge acidophil adenoma; extensive destruction ofpituitary substance, compression of optic chiasm,invasion of third ventricle and floor of sellaGrowth Hormone–Secreting Adenomas The effects of growth hormone–secreting adenomas varydepending on size and growth rate as well as invasiveness.
Large tumors cause destruction of the pituitaryand deficiency of other pituitary hormones and may affect the optic chiasm and vision. Growth hormoneexcess produces acromegaly in adults (right panel), with protrusion of the jaw, macroglossia, and othereffects.General Principles of Endocrinology and Pituitary and Hypothalamic HormonesShort-loop feedback319Other modulating factorsHoursDopamineProlactinProlactinDopamine(PIF)PIF feedbackinhibitionTRHProlactinEstrogenProlactin-inhibiting factor (PIF), thought to be dopamine, modulates prolactin secretion. Elevated prolactin levels increase PIF secretionand cause feedback inhibition of prolactin secretion (short-loop feedback inhibition).
Estrogen and TRH stimulate prolactin secretion.Breast developmentPregnancyProlactinLactationProlactinProlactinGHEstrogenOxytocinEstrogenEstrogenProgesteroneProgesteroneProgesteroneAdrenocorticoidsProlactin, along with GH, estrogen,progesterone, and adrenocorticoids,is necessary for breast development.In pregnancy, elevated prolactin, estrogen andprogesterone increase alveolobular development.High estrogen levels inhibit lactation.FetusSudden decrease in estrogen andprogesterone in presence of prolactinresults in milk production.
Oxytocinstimulates milk release.Variations in prolactin levels by age or conditionPreReproductivePregnancyPostpartummenarche yearsMenopauseEstrogen7Prolactin(ng/mL) 20018016014012010080604020Months14 21OnsetoflaborNursingDeliveryPuberty(nights)Non-nursingFigure 26.9 Prolactin Prolactin synthesis and release by the anterior pituitary is mainly under tonicnegative control by dopamine (prolactin inhibitory factor, PIF). Its major functions are in breast development,pregnancy, and lactation. Its levels are elevated during fetal development, pregnancy, and the postpartumperiod (if the woman is breastfeeding).
TRH, thyrotropin-releasing hormone.PROLACTINRegulation of Prolactin SecretionProlactin is a 198 amino acid, single-chain polypeptide structurally related to growth hormone. It is secreted at low levelsexcept in pregnant and lactating women, in whom the numberof lactotrophs in the anterior pituitary is increased and plasmaprolactin is elevated. The hormone’s main actions are to stimulate breast development and milk production, as suggestedby its name.The hypothalamic hormones involved in the regulation of prolactin secretion by the anterior pituitary are(Fig. 26.9):■Dopamine (also referred to as prolactin inhibitoryfactor in this context), which inhibits prolactinrelease, and320■Endocrine PhysiologyThyrotropin-releasing hormone (TRH), which stimulates release of prolactin in addition to thyroid-stimulating hormone.Prolactin exerts negative feedback effects on its own releaseby stimulating secretion of dopamine by the hypothalamus.Effects of ProlactinIn most instances, prolactin synthesis and release is primarilyunder the inhibitory influence of dopamine.
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