Physiology_Levy

Physiology_Levy. The Neurohypophysis The pars nervosa is a neurovascular structure that is the site of neurohormone release adjacent to a rich capillary bed. The peptide hormones that are released are antidiuretic hormone (ADH, or arginine vasopressin) and oxytocin. The cell bodies of the neurons that project to the pars nervosa are located in the supraoptic nuclei (SON) and paraventricular nuclei (PVN) of the hypothalamus (a nucleus refers to a collection of neuronal cell bodies residing within the central nervous system (CNS); a ganglion is a collection of neuronal cell bodies residing outside the CNS). The large cell bodies of these neurons are described as magnocellular, and they project axons down the infundibular stalk as the hypothalamohypophyseal tracts. Individual magnocellular neurons are hormone specific, producing •Fig. 41.1 Cross-sectionalimageoftheheaddemonstratingtheproximityofthehypothalamusandpituitaryglandandtheirconnectionbyaneurohypophyseal(pituitary)stalk.


Physiology_Levy

Physiology_Levy. either ADH or oxytocin. These axons terminate in the pars nervosa ( Fig. 41.3 ). In addition to axonal processes and termini from the SON and PVN, there are glial-like support cells called pituicytes. The posterior pituitary is extensively vascularized and the capillaries are fenestrated, thereby facilitating diffusion of hormones into the systemic circulation. Synthesis of ADH and Oxytocin ADH and oxytocin are small peptides (nine amino acids) that differ in only two amino acids, yet they have limited overlapping activity. ADH and oxytocin are synthesized as preprohormones (


Physiology_Levy

Physiology_Levy. ADH and oxytocin are small peptides (nine amino acids) that differ in only two amino acids, yet they have limited overlapping activity. ADH and oxytocin are synthesized as preprohormones ( Fig. 41.4 ). Each prohormone harbors the structure of oxytocin or ADH and a co-secreted peptide, either neurophysin I (associated with ADH) or neurophysin II (associated with oxytocin). These preprohormones are called preprovasophysin and preprooxyphysin. The N-terminal signal peptide is cleaved as the peptide is transported into the endoplasmic reticulum. In cell bodies within the SON and PVN, the prohormones are packaged in the endoplasmic reticulum and Golgi apparatus in membrane-bound secretory granules (


Physiology_Levy

Physiology_Levy. Fig. 41.5 ). The secretory granules are conveyed through a “fast” (i.e., millimeters per hour) adenosine triphosphate (ATP)-dependent axonal transport mechanism down the infundibular stalk to axonal termini in the pars nervosa. During transit of the secretory granule, the prohormones are proteolytically cleaved to produce equimolar amounts of hormone and neurophysin. Secretory granules containing fully processed peptides are stored in the axonal termini. Expansions of the termini due to the presence of stored secretory granules can be observed by light microscopy and are termed Herring bodies.


Physiology_Levy

Physiology_Levy. ADH and oxytocin are released from the pars nervosa in response to stimuli that are primarily detected at the cell body and its dendrites in the SON and PVN. These stimuli are mainly in the form of neurotransmitters released from hypothalamic interneurons. With sufficient stimulus the neurons will depolarize and propagate an action potential down the axon. At the axonal termini the action potential increases intracellular [Ca++] and results in a stimulus-secretion response, with exocytosis of ADH or oxytocin along with neurophysins into the extracellular fluid of the pars nervosa (see Fig. 41.5). Hormones and neurophysins enter the peripheral circulation, and both can be measured in blood. Actions and Regulation of ADH and Oxytocin


Physiology_Levy

Physiology_Levy. Fig. 41.5). Hormones and neurophysins enter the peripheral circulation, and both can be measured in blood. Actions and Regulation of ADH and Oxytocin ADH acts primarily at the kidney to retain water (antidiuresis). The actions of ADH and regulation of ADH secretion were described in . Oxytocin primarily acts on the pregnant uterus to induce labor and on myoepithelial cells of the breast to promote milk letdown during nursing. The actions and regulation of oxytocin are discussed in The Adenohypophysis The pars distalis is composed of five endocrine cell types that produce six hormones ( Table 41.1 ). Because of the histological staining properties of the cell types, the corticotropes, thyrotropes, and gonadotropes are referred to as pituitary basophils, whereas the somatotropes and lactotropes are referred to as pituitary acidophils (see Fig. 41.2B


Physiology_Levy

Physiology_Levy. Before discussing the individual hormones of the adenohypophysis, it is important to understand the structural •Fig. 41.2 A,Grossstructureofthepituitarygland.Thepituitaryglandisbelowthehypothalamusandisconnectedtoitbythepituitarystalk.Theglandsitswithinthesellaturcica,afossawithinthesphenoidbone,andiscoveredbyaduralreflection,thediaphragmasellae.Theparsdistalismakesupmostoftheanteriorpituitary.B,Theparsdistalisisderivedfromepithelialtissuethatiscomposedofacidophils (A)(somatotropesandlactotropes)andbasophils(B)(thyrotropes,gonadotropes,andcorticotropes).C,Theposteriorpituitaryisderivedfromneuraltissueandhasahistologicalappearanceofnonmyelinatednerves.Cp,chromophobes;H,Herringbodies.(A,ModifiedfromStevensA.In:LoweJS[ed].Human Histology. 3rded.Philadelphia:Elsevier;2005.BandC,FromYoungBetal[eds].Wheater’s Functional Histology. 5thed.Philadelphia:ChurchillLivingstone;2006.) •Fig. 41.3


Physiology_Levy

Physiology_Levy. Histology. 3rded.Philadelphia:Elsevier;2005.BandC,FromYoungBetal[eds].Wheater’s Functional Histology. 5thed.Philadelphia:ChurchillLivingstone;2006.) •Fig. 41.3 Magnocellularneuronsofthehypothalamus(paraven-tricularandsupraopticnuclei)projecttheiraxonsdowntheinfundibularprocessandterminateintheparsnervosa(posteriorlobe),wheretheyreleasetheirhormones(eitherADHoroxytocin)intoacapillarybed.(ModifiedfromLarsenPRetal[eds].Williams Textbook of Endocrinol-ogy. 10thed.Philadelphia:Saunders;2003.)Capilary bed Anterior lobe of pituitary Optic chiasm Hypothalamus Posterior lobe of pituitary Magnocellular neurosecretory cells


Physiology_Levy

Physiology_Levy. Becauseposteriorpituitaryhormonesaresynthesizedinthehypothalamusratherthanthepituitary,hypophysectomy (pituitaryremoval)doesnotnecessarilypermanentlydisruptsynthesisandsecretionofthesehormones.Immediatelyafterhypophysectomy,secretionofthehormonesdecreases.However,overaperiodofweekstheseveredproximalendofthetractwillshowhistologicalmodificationandpituicyteswillformaroundtheneuronterminals.Secretoryvacuolesareseen,andsecretionofhormoneresumesfromthisproximalend.Secretionofhormonecanevenpotentiallyreturntonormallevels.Incontrast,alesionhigheruponthepituitarystalkcanleadtolossofneuronalcellbodiesinthePVNandSON. and functional organization of the adenohypophysis in the context of the endocrine axes (


Physiology_Levy

Physiology_Levy. and functional organization of the adenohypophysis in the context of the endocrine axes ( Fig. 41.6 41.1 ). Each endocrine axis is composed of three levels of endocrine cells: (1) hypothalamic neurons, (2) anterior pituitary cells, and (3) peripheral endocrine glands. Hypothalamic neurons release specific hypothalamic releasing hormones (designated XRH in this generic scheme) that stimulate secretion of specific pituitary tropic hormones (XTH). In some cases, production of a pituitary tropic hormone is secondarily regulated by a release-inhibiting hormone (XIH). Pituitary tropic hormones then act on specific peripheral target endocrine glands and stimulate them to release peripheral hormones (X). The peripheral hormone X has two general functions: it regulates several aspects of human physiology, and it negatively feeds back on the pituitary gland and hypothalamus to inhibit production and secretion of tropic hormones and releasing hormones, respectively (see Fig. 41.6


Physiology_Levy


Physiology_Levy

Physiology_Levy. mutationshavedwarfismandintellectualdisability.Thenuclearhormonereceptor–relatedtranscriptionfactorsteroidogenic factor-1 (SF-1) wasoriginallyidentifiedintheadrenalcortexandgonadsasaregulatorofsteroidogenicenzymegeneexpression.SF-1isalsoexpressedinGnRHneuronsinthehypothalamusandinpituitarygonadotropes,whereitregulatestranscriptionofLHandFSH.MutationsintheSF1 genedisruptadrenalandgonadalfunction,includinglossofgonadotropesinthepituitarygland.TPIT isatranscriptionfactorinvolvedinthedifferentiationofcorticotropes.TPIT,actingwithothertranscriptionfactors,promotesdifferentiationofcorticotropesandexpressionofthePOMC gene(seeCorticotropessection).MutationsinthehumanTPIT generesultinisolated ACTH deficiency. Thisresultsinaformofsecondary adrenal insufficiency thatrequireslifelongreplacementwithglucocorticoids(see


Physiology_Levy

Physiology_Levy. The hypothalamic regulation of anterior pituitary function is neurohormonal. An area of the hypothalamus collectively referred to as the hypophysiotropic (i.e., stimulatory to the hypophysis) region contains nuclei composed of small, or parvocellular, cell bodies that project axons to the Transcription, excision, splicing •Fig. 41.4 Synthesisandprocessingofpreprovasopressinorpreprooxytocin. median eminence. They are distinct from the magnocellular neurons of the PVN and SON that project to the pars nervosa. Parvocellular neurons secrete releasing hormones from their axonal termini at the median eminence (Fig.


Physiology_Levy

Physiology_Levy. 41.7 ). The releasing hormones enter a primary plexus of fenestrated capillaries and are then conveyed to a second capillary plexus located in the pars distalis by the hypothalamohypophyseal portal vessels (a portal vessel is defined as a vessel that begins and ends in capillaries without going through the heart). At the secondary capillary plexus, the releasing hormones diffuse out of the vasculature and bind to their cognate receptors on specific cell types within the pars distalis. The neurovascular link (i.e., pituitary stalk) between the hypothalamus and pituitary is somewhat fragile and can be disrupted by physical trauma, surgery, or hypothalamic disease. Damage to the stalk and subsequent functional isolation of the anterior pituitary result in a decline in all anterior pituitary tropic hormones except prolactin (discussed later).


Physiology_Levy

Physiology_Levy. The cells of the adenohypophysis make up the intermediate level of the endocrine axes. The adenohypophysis secretes protein hormones that are referred to as tropic hormones—adrenocorticotropic hormone (ACTH, also called corticotropin), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin (PRL) (see Table 41.1). With a few exceptions, tropic hormones bind to their cognate receptors on peripheral endocrine glands. Because of this arrangement, pituitary tropic hormones generally do not directly regulate physiological responses (see Chapter 38). The endocrine axes have the following important features: 1.


Physiology_Levy

Physiology_Levy. Chapter 38). The endocrine axes have the following important features: 1. The activity of a specific axis is normally maintained at a set point, which varies from individual to individual, usually within a normal range. The set point is determined by the integration of hypothalamic stimulation and peripheral hormone negative feedback. Importantly, negative feedback generally is not exerted by the physiological responses regulated by a specific endocrine axis but by the peripheral hormone itself acting on the pituitary and hypothalamus (see


Physiology_Levy

Physiology_Levy. Fig. 41.6 ). Thus if the level of a peripheral hormone drops, secretion of hypothalamic releasing hormones and pituitary tropic hormones will increase. As the level of peripheral hormone rises, the hypothalamus and pituitary will decrease secretion because of negative feedback. Although certain nonendocrine physiological parameters (e.g., acute hypoglycemia) can regulate some endocrine axes, the axes function semiautonomously with respect to the physiological changes they produce. This configuration means a peripheral hormone (e.g., thyroid hormone) can regulate multiple organ systems without these organ systems exerting competing negative-feedback regulation of the hormone. Clinically this partial autonomy means that multiple aspects of a patient’s physiology are at the mercy of whatever derangements might exist within a specific axis. 2.


Physiology_Levy

Physiology_Levy. Hypothalamic hypophysiotropic neurons are often secreted in a pulsatile manner and are entrained to daily and seasonal rhythms through CNS input. Additionally, hypothalamic nuclei receive a variety of neuronal inputs from higher and lower levels of the brain. These can be • Fig. 41.5 Synthesis, processing, and transport of preprovasopressin. Human ADH (also called arginine vasopressin [AVP]) is synthesized in the hypothalamic magnocellular cell bodies and packaged into neurosecretory granules. During intraaxonal transport of the granules down the infundibular process to the pars nervosa, provasopressin is proteolytically cleaved into the active hormone (AVP = ADH), neurophysin (NP), and a C-terminal glycoprotein (GP). NP arranges into tetramers that bind five AVP molecules. All three fragments are secreted from axonal termini in the pars nervosa (posterior pituitary) and enter the systemic blood. Only AVP (ADH) is biologically active. (Modified from Larsen PR et al [eds]. Williams


Physiology_Levy

Physiology_Levy. Textbook of Endocrinology. 10th ed. Philadelphia: Saunders; 2003.)


Physiology_Levy

Physiology_Levy. X Primary Endocrine Disease (Thyroid, adrenal cortex, gonads, liver) •Fig. 41.6 Negative-feedbackloopsregulatinghormonesecretioninatypicalhypothalamus-pituitaryperipheralglandaxis.X,peripheralglandhormone;XIH,hypothalamic-inhibitinghormone;XRH,hypothalamic-releasinghormone;XTH,pituitarytropichormone. short-term (e.g., various stress/infections) or long-term (e.g., onset of reproductive function at puberty) inputs. Thus inclusion of the hypothalamus in an endocrine axis allows integration of a considerable amount of information for setting or changing the set point of that axis. Clinically this means a broad range of complex neurogenic states can alter pituitary function. Psychosocial dwarfism is a striking example in which children subject to abuse or intense emotional stress have lower growth rates as a result of decreased growth hormone secretion by the pituitary gland.


Physiology_Levy

Physiology_Levy. 3. Abnormally low or high levels of a peripheral hormone (e.g., thyroid hormone) may be due to a defect at the level of the peripheral endocrine gland (e.g., thyroid), the pituitary gland, or the hypothalamus. Such lesions are referred to as primary, secondary, and tertiary endocrine disorders, respectively (see Fig. 41.6 ). A thorough understanding of the feedback relationships within an axis allows the physician to determine where the defect lies. Primary endocrine deficiencies tend to be the most severe because they often involve complete absence of the peripheral hormone. Endocrine Function of the Adenohypophysis The adenohypophysis consists of the following endocrine cell types: corticotropes, thyrotropes, gonadotropes, somatotropes, and lactotropes (see Table 41.1


Physiology_Levy

Physiology_Levy. The adenohypophysis consists of the following endocrine cell types: corticotropes, thyrotropes, gonadotropes, somatotropes, and lactotropes (see Table 41.1 Corticotropes stimulate the adrenal cortex as part of the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropes produce the hormone ACTH (corticotropin), which stimulates two zones of the adrenal cortex (see ). ACTH is a 39–amino acid peptide that is synthesized as part of a larger prohormone called proopiomelanocortin (POMC). Thus corticotropes are also referred to as POMC cells. POMC harbors the peptide sequence for ACTH, two isoforms of melanocyte-stimulating hormone (MSH), endorphins (endogenous opioids), and enkephalins ( Fig.


Physiology_Levy

Physiology_Levy. Fig. 41.8 ). However, the human corticotrope expresses only pro-hormone convertase-1, which produces ACTH as the sole active hormone secreted by these cells. The other fragments that are cleaved from POMC are the N-terminal fragment and β-lipotropic hormone (β-LPH), neither of which plays a physiological role in humans.


Physiology_Levy

Physiology_Levy. 740 SECTION8Berne & Levy Physiology •Fig. 41.7 Neurovascularlinkbetweenthehypothalamusandtheanteriorlobe(parsdistalis)ofthepitu-itary.Parvicellular“hypophysiotropic”neurosecretoryneuronswithinvarioushypothalamicnucleiprojectaxonstothemedianeminence,wheretheysecretereleasinghormones(RHs).RHsflowdownthepituitarystalkinthehypothalamohypophysealportalvesselstotheanteriorpituitary.RHs(andrelease-inhibitinghormones[seetext])regulatesecretionoftropichormonesfromthefivecelltypesoftheanteriorpituitary.(FromLarsenPRetal[eds].Williams Textbook of Endocrinology. 10thed.Philadelphia:Saunders;2003.)Hormone-secreting cells Anterior lobe of pituitary Capillary beds Hypothalamohypophyseal portal vessels Hypothalamus Median eminence Parvocellular neurosecretory cells Hypophysiotropic hormones released Hormone transport in axons Hormone transport in blood Hormone transport in blood Stimulation or inhibition of anterior pituitary hormone release Action on endocrine glands


Physiology_Levy

Physiology_Levy. ACTH circulates as an unbound hormone and has a short half-life of about 10 minutes. It binds to the melanocortin-2 receptor (MC2R) on cells in the adrenal cortex ( Fig. 41.9 ). ACTH acutely increases cortisol and adrenal androgen production by increasing expression of steroidogenic enzyme genes. In the long term, ACTH promotes growth and survival of two zones within the adrenal cortex (see ACTH is under stimulatory control by the hypothalamus. A subset of parvocellular hypothalamic neurons expresses the peptide procorticotropin-releasing hormone (pro-CRH) (see Table 41.1). Pro-CRH is processed to CRH, an amidated 41–amino acid peptide. CRH acutely stimulates ACTH secretion and increases transcription of the POMC gene. The parvocellular neurons that express CRH also express ADH, which potentiates the action of CRH on corticotropes. ACTH secretion has a pronounced diurnal pattern, with a peak in early morning and a nadir


Physiology_Levy

Physiology_Levy. Atsupraphysiologicallevels,ACTH causesdarkeningoftheskin(e.g.,inCushing’sdisease).KeratinocytesinthebasallayeroftheepidermisalsoexpressthePOMCgenebutprocessittoα-MSH insteadofACTH.Keratinocytessecreteα-MSHinresponsetoultravioletlight,andα-MSHactsasaparacrinefactoronneighboringmelanocytestodarkentheskin.α-MSHbindstotheMC1R onmelanocytes.Atveryhighlevels,ACTHcancross-reactwiththeMC1Rreceptoronskinmelanocytes(see Fig.41.9 ).ThusincreasedskinpigmentationisoneindicatorofexcesscirculatingACTH. Fig. 41.10). In addition, secretion of CRH—and hence secretion of ACTH—is pulsatile. There are multiple regulators of the HPA axis, and many of them are mediated through the CNS ( Fig. 41.11). Many types of stress, both neurogenic (e.g., fear) and systemic TABLE 41.1


Physiology_Levy

Physiology_Levy. There are multiple regulators of the HPA axis, and many of them are mediated through the CNS ( Fig. 41.11). Many types of stress, both neurogenic (e.g., fear) and systemic TABLE 41.1 Adenohypophysis Cell Types: Hormonal Production and Action, Hypothalamic Regulation, and Feedback Regulation •Fig. 41.8 Theoriginalgenetranscriptofproopiomelanocortincontainsstructuresofmultiplebioactivecompounds.ACTH,adrenocorticotropichormone;CLIP,corticotropin-likeintermediatepeptide;MSH,melanocyte-stimulatinghormone.NotethatACTHistheonlybioactivepeptidereleasedbythehumancorticotrope.


Physiology_Levy

Physiology_Levy. •Fig. 41.9 NormallevelsofACTHactontheMC2Rtoincreasecortisol.SupraphysiologicallevelsofACTHduetodecreasedcortisolproductionactonboththeMC2RandtheMC1Ronmelanocytesandcauseskindarkening.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)UV light Keratinocytes in skin Melanocytes in skin PKA Pituitary corticotrope POMC expression ACTH secretion ACTH (physiological levels) Cortisol Diverse physiological effects ACTH (supraphysiological levels) In particular ° Blood glucose ˛ Inflammatory response High affinity binding to MC2R Low affinity binding to MC1R • Loss of feedback in Addison’s disease Physiological, high affinity PKA Steroidogenesis Cell growth ˝-MSH ° POMC expression Skin darkening Release of CRH at median eminence CRH neurons Cortisol (−) Cortisol (−) CRH CRH-R1 Adrenal cortex PKA ° Melanin synthesis and dispersal (e.g., infection), stimulate ACTH. The stress effects are mediated through CRH and ADH via the CNS. The response to many forms of


Physiology_Levy

Physiology_Levy. (−) CRH CRH-R1 Adrenal cortex PKA ° Melanin synthesis and dispersal (e.g., infection), stimulate ACTH. The stress effects are mediated through CRH and ADH via the CNS. The response to many forms of severe stress can persist despite negative feedback from high cortisol levels. This means the hypothalamus has the ability to alter the set point of the HPA axis in response to stress. Severe chronic depression can reset the HPA axis as a result of hypersecretion of CRH and is a factor in the development of tertiary hypercortisolism.


Physiology_Levy

Physiology_Levy. Cortisol exerts negative feedback on the pituitary, where it suppresses POMC gene expression and ACTH secretion, and on the hypothalamus, where it decreases pro-CRH gene expression and release of CRH. Because cortisol has profound effects on the immune system (see ), the HPA axis and the immune system are closely coupled. Moreover, cytokines—particularly interleukin (IL)-1, IL-2, and IL-6—stimulate the HPA axis. Thyrotropes regulate thyroid function by secreting the hormone TSH (thyrotropin) as part of the hypothalamic-pituitary-thyroid axis. TSH is one of three pituitary glycoprotein hormones (see Table 41.1) that also include FSH and LH (discussed later). TSH is a heterodimer composed of an α subunit, called the α-glycoprotein subunit (α-GSU), and a β subunit (β-TSH) (


Physiology_Levy

Physiology_Levy. Table 41.1) that also include FSH and LH (discussed later). TSH is a heterodimer composed of an α subunit, called the α-glycoprotein subunit (α-GSU), and a β subunit (β-TSH) ( Fig. 41.12 ). The α-GSU is common to TSH, FSH, and LH, whereas the β subunit is hormone specific (i.e., β-TSH, β-FSH, and β-LH are all unique). Glycosylation of the subunits increases their stability in circulation and enhances the affinity and specificity of the hormones for their receptors. The half-lives of TSH, FSH, and LH (and an LH-like placental glycoprotein hormone, human chorionic gonadotropin [hCG]) are relatively long, ranging from tens of minutes to several hours. TSH binds to the TSH receptor on thyroid follicle cells (see Chapter 42). As discussed in


Physiology_Levy

Physiology_Levy. TSH binds to the TSH receptor on thyroid follicle cells (see Chapter 42). As discussed in Chapter 42, production of thyroid hormones is a complex multistep process, and TSH stimulates essentially every aspect of thyroid function. TSH also has a strong tropic effect and stimulates hypertrophy, hyperplasia, and survival of thyroid epithelial cells. In geographical regions where the availability of iodide is limited (iodide is required for the synthesis of thyroid hormone), TSH levels are elevated because of reduced negative feedback. Elevated TSH levels can produce striking growth of the thyroid, producing a bulge in the neck called a goiter. •Fig. 41.10 DiurnalpatternofserumACTH.(ModifiedfromPor-terfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)Awake Sleep Serum ACTH level The pituitary thyrotrope is stimulated by the releasing hormone thyrotropin-releasing hormone (TRH) (see


Physiology_Levy

Physiology_Levy. The pituitary thyrotrope is stimulated by the releasing hormone thyrotropin-releasing hormone (TRH) (see Table 41.1). TRH, produced by a subset of parvocellular •Fig. 41.11 Hypothalamic-pituitary-adrenalaxisillustratingfactorsregulatingsecretionofcorticotropin-releasinghormone(CRH).ACTH,adrenocorticotropichormone.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)CRH Physical Diurnal rhythms Emotional Others Set point ACTH Corticotroph Long feedback (cortisol) Short feedback (ACTH) Chemical (hypoglycemia) •Fig. 41.12 Pituitaryglycoproteinhormones.hCGismadebytheplacenta(see )andbindstotheLHreceptor.FSH,follicle-stimulatinghormone;hCG,humanchorionicgonadotropin;LH,luteinizinghormone;TSH,thyroid-stimulatinghormone.˜-TSH subunit ˜-FSH subunit ˜-LH subunit ˜-hCG subunit TSH FSH LH hCG TSH receptor FSH receptor LH receptor LH receptor Plus °-glycoprotein subunit (°-GSU)


Physiology_Levy

Physiology_Levy. Ca++ and PKC TSH synthesis TSH secretion TSH PKA • All aspects of thyroid hormone synthesis and secretion • Cell growth CNS inputs Diurnal rhythm T3 (−) T4, T 3 T3 (−) TRH TRH receptor TSH receptor Pituitary thyrotrope Thyroid epithelial cell •Fig. 41.13 Hypothalamic-pituitary-thyroidaxis.PKA,proteinkinaseA;PKC,proteinkinaseC;T3,triiodothyronine(activeformofthyroidhormone);T4,thyroxine;TRH,thyrotropin-releasinghormone;TSH,thyroid-stimulatinghormone.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.) hypothalamic neurons, is a tripeptide with cyclization of a glutamine at its N-terminus (pyro-Glu) and an amidated C-terminus. TRH is synthesized as a larger prohormone that contains six copies of TRH within its sequence. It binds to the TRH receptor on thyrotropes (Fig. 41.13 ). TRH neurons are regulated by numerous CNS-mediated stimuli, and TRH is released according to a diurnal rhythm (highest during overnight hours, lowest around dinner time). TRH


Physiology_Levy

Physiology_Levy. (Fig. 41.13 ). TRH neurons are regulated by numerous CNS-mediated stimuli, and TRH is released according to a diurnal rhythm (highest during overnight hours, lowest around dinner time). TRH secretion is also regulated by stress, but in contrast to CRH, stress inhibits secretion of TRH. This includes physical stress, starvation, and infection. Triiodothyronine (T3) and thyroxine (T4) (the latter via type 2 deiodinase-mediated conversion to T3; see ) negatively feed back on both pituitary thyrotropes and TRH-producing neurons. Thyroid hormone represses both β-TSH expression and the sensitivity of pituitary thyrotropes to TRH while also inhibiting TRH production and secretion by parvocellular neurons.


Physiology_Levy

Physiology_Levy. Duringembryonicdevelopment,GnRHneuronsmigratetothemediobasalhypothalamusfromthenasalplacode.PatientswithKallmann syndrome havetertiary hypogonadotropic hypogonadism, oftenassociatedwithlossofthesenseofsmell(anosmia).ThisisduetoamutationintheKAL gene, whichresultsinfailureoftheGnRHneuronalprecursorstoproperlymigratetothehypothalamusandestablishaneurovascularlinktotheparsdistalis. The Gonadotrope The gonadotrope secretes FSH and LH (collectively called gonadotropins) and regulates the function of gonads in both sexes. As such the gonadotrope plays an integral role in the hypothalamic-pituitary-testis axis and the hypothalamic-pituitary-ovarian axis ( Fig. 41.14


Physiology_Levy

Physiology_Levy. Fig. 41.14 FSH and LH are segregated into different secretory granules and are not co-secreted in equimolar amounts (in contrast to ADH and neurophysin, for example). This allows independent regulation and secretion of FSH/LH by gonadotropes. The actions of FSH and LH on gonadal function are complex, especially in women, and will be discussed in detail in . In general, gonadotropins promote testosterone secretion in men and estrogen and progesterone secretion in women. FSH also increases secretion of a transforming growth factor (TGF)-β–related protein hormone called inhibin in both sexes. FSH and LH secretion are regulated by one hypothalamic releasing hormone, gonadotropin-releasing hormone (GnRH; formerly called LHRH). GnRH is a 10–amino acid peptide produced by a subset of parvocellular hypothalamic GnRH neurons (see


Physiology_Levy

Physiology_Levy. Fig. 41.14 ). GnRH is produced as a larger prohormone and, as part of its processing to a decapeptide, is modified with a cyclized glutamine (pyro-Glu) at its N-terminus and an amidated C-terminus. GnRH is released in a pulsatile manner ( Fig. 41.15 ), and both the pulsatile secretion and the frequency of the pulses have important effects on the gonadotrope. Continuous infusion of GnRH downregulates the GnRH receptor, thereby resulting in a decrease in FSH and LH secretion. In contrast, pulsatile secretion does not desensitize the gonadotrope to GnRH, and FSH and LH secretion is normal. At a frequency of one pulse per hour, GnRH preferentially increases LH secretion ( Fig. 41.16 ). At a slower frequency of one pulse per 3 hours, GnRH preferentially increases FSH secretion. Gonadotropins increase sex steroid synthesis (see Fig. 41.14 ). In men, testosterone and estrogen negatively feed back at the level of the pituitary and the hypothalamus.


Physiology_Levy

Physiology_Levy. Fig. 41.14 ). In men, testosterone and estrogen negatively feed back at the level of the pituitary and the hypothalamus. Ca++, PKC, other pathways? SlowFast GnRH (+) pulses GnRH pulses LH synthesis and secretion FSH synthesis and secretion FSHLH PKA Inhibin Pulsatile release of GnRH at median eminence PubertyCNS Opioids Stress Prolactin (−)Sex steroids GnRH neurons inputs (+) (−) (−) GnRH Sex steroids GnRH receptor FSH receptorLH receptor Pituitary gonadotrope Gonadal cell types Steroidogenesis Gametogenesis •Fig. 41.14 Hypothalamic-pituitary-gonadalaxis.FSH,follicle-stimulatinghormone;GnRH,gonadotropin-releasinghormone;LH,luteinizinghormone.(ModifiedfromPorterfieldSP,WhiteBA.Endocrine Physiology. 3rded.Philadelphia:Mosby;2007.)


Physiology_Levy

Physiology_Levy. Physiology. 3rded.Philadelphia:Mosby;2007.) Exogenous progesterone also inhibits gonadotropin function in men and has been considered as a possible component of a male contraceptive pill. Additionally, inhibin negatively feeds back selectively on FSH secretion in men and women. In women, progesterone and testosterone negatively feed back on gonadotropic function at the level of the hypothalamus and pituitary. At low doses, estrogen also exerts negative feedback on FSH and LH secretion. However, high estrogen levels maintained for 3 days cause a surge in LH and to a lesser extent FSH secretion. This positive feedback, which is critical in promoting ovulation, is observed at the hypothalamus and pituitary. At the hypothalamus, GnRH pulse amplitude and frequency increase. At the pituitary, high estrogen levels greatly increase the sensitivity of the gonadotrope to GnRH, both by increasing GnRH receptor levels and by enhancing postreceptor signaling (see The Somatotrope


Physiology_Levy

Physiology_Levy. The Somatotrope The somatotrope produces GH (somatotropin) and is part of the hypothalamic-pituitary-liver axis ( Fig. 41.17 ). A major target of GH is the liver, where it stimulates production of insulinlike growth factor (IGF)-I. GH is a 191–amino acid protein that is similar to PRL and human placental lactogen (hPL); accordingly there is some overlap in activity among these hormones. Multiple forms of GH 746 SECTION8Berne & Levy Physiology 1.8 1.2 0.6 0 12 10 8 6 1200 1300 1400 1500 1600 Hours GnRH(pg/10 min) LH(ng/mL) Fig. 41.15 FluctuationofperipheralveinplasmaLHlevelsandportalveinplasmaGnRHlevelsinunanesthetized,ovariectomizedfemalesheep.EachpulseofLHiscoordinatedwithapulseofGnRH.ThissupportstheviewthatpulsatilityofLHreleaseisdependentonpulsatilestimulationofthepituitarybyGnRH.(FromLevineJetal.Endocrinology 1982;111:1449.)


Physiology_Levy

Physiology_Levy. Fig. 41.16 Frequency-encodedregulationofFSHandLHsecretionfromgonadotropes.AhighfrequencyofGnRH(1pulse/hr)preferentiallystimulatesLHsecretion,whereasaslowerfrequencyofGnRHpromotesFSHsecretion.(FromLarsenPRetal[eds].Williams Textbook of Endocrinology. 10th ed.Philadelphia:Saunders;2003.) are present in serum, with the 191–amino acid (22-kDa) form representing approximately 75% of circulating GH. The GH receptor is a member of the cytokine/GH/PRL/ erythropoietin receptor family and as such is linked to the JAK/STAT signaling pathway (see ). Human GH can also act as an agonist of the PRL receptor. About 50% of the 22-kDa form of GH in serum is bound to GH-binding protein (GHBP), which is derived from the N-terminal portion (the extracellular domain) of the GH receptor. Individuals with Laron syndrome, who lack normal GH receptors but have normal GH secretion, do not have detectable GHBP in their serum. GHBP reduces renal clearance and thus increases the biological half-life of GH, which


Physiology_Levy

Physiology_Levy. syndrome, who lack normal GH receptors but have normal GH secretion, do not have detectable GHBP in their serum. GHBP reduces renal clearance and thus increases the biological half-life of GH, which is about 20 minutes. The liver and kidney are major sites of GH degradation.


Physiology_Levy

Physiology_Levy. GH secretion is under dual positive/negative control by the hypothalamus (see Fig. 41.17 ). The hypothalamus predominantly stimulates GH secretion via the peptide growth •Fig. 41.17 Hypothalamic-pituitary-liveraxis.ALS,acidlabilesubunit;GHBP,growthhormone–bindingprotein;GHRH,growthhormone–releasinghormone;IGFBP,insulinlikegrowthfactor–bindingprotein;IGF-I,insulinlikegrowthfactorI;SS,somatostatin.(FromPorterfieldSP,WhiteBA.Endocrine Physiology.


Physiology_Levy

Physiology_Levy. 3rded.Philadelphia:Mosby;2007.) hormone–releasing hormone (GHRH). This hormone is a member of the vasoactive intestinal polypeptide (VIP)/ secretin/glucagon family and is processed from a larger prohormone into a 44–amino acid peptide with an amidated C-terminus. GHRH enhances GH secretion and GH gene expression. The hypothalamus inhibits pituitary GH synthesis and release via the peptide somatostatin. In the anterior pituitary, somatostatin inhibits release of GH and TSH. GH secretion is also stimulated by ghrelin, which acts through the GH secretagogue receptor on somatotropes. Ghrelin is primarily produced by the stomach but is also expressed in the hypothalamus. Ghrelin increases appetite and may serve as a signal to coordinate nutrient acquisition with growth. The primary negative feedback on the somatotrope is exerted by IGF-I (see


Physiology_Levy

Physiology_Levy. The primary negative feedback on the somatotrope is exerted by IGF-I (see Fig. 41.17). GH stimulates IGF-I pro duction by the liver, and IGF-I then inhibits GH synthesis and secretion by the pituitary and hypothalamus in a classic “long feedback” loop. In addition, GH itself exerts negative feedback on release of GHRH through a “short feedback” loop. GH also increases somatostatin release.


Physiology_Levy

Physiology_Levy. GH secretion, like ACTH, shows prominent diurnal rhythms, with peak secretion occurring in the early morning just before awakening. Its secretion is stimulated during deep slow-wave sleep (stages III and IV). GH secretion is lowest during the day. This rhythm is entrained to sleep-wakefulness patterns rather than light-dark patterns, so a phase shift occurs in people who work night shifts. As is typical of anterior pituitary hormones, GH secretion is pulsatile. Levels of GH in serum vary widely (0–30 ng/ mL, with most values usually falling between 0 and 3). Because of this marked variation and the heterogeneity of circulating GH, measurement of serum GH levels is of limited clinical utility. Since IGF-I secretion is regulated by GH and possesses a longer half-life that buffers pulsatile and diurnal changes in GH secretion, it may be used to assess the status of the GH axis, especially in young patients.


Physiology_Levy

Physiology_Levy. GH secretion is differentially regulated depending on the physiological state. GH is classified as one of the “stress hormones” and is increased by neurogenic and physical stress. It promotes lipolysis, increases protein synthesis, and antagonizes the ability of insulin to reduce blood glucose levels. It is not surprising, therefore, that acute hypoglycemia is a stimulus for GH secretion and GH is classified as a hyperglycemic hormone. A rise in the serum concentration of some amino acids also stimulates GH secretion; administration of arginine is used for provocative testing of GH secretion. In contrast, an increase in blood glucose or free fatty acids inhibits secretion of GH. Obesity also inhibits GH secretion, in part because of insulin resistance (relative hyperglycemia) and increased circulating free fatty acids. Conversely, exercise and starvation stimulate GH secretion. The lifetime pattern of GH secretion is shown in Fig.


Physiology_Levy

Physiology_Levy. The lifetime pattern of GH secretion is shown in Fig. 41.18 . GH secretion increases in the neonatal period as growth becomes GH and IGF-I dependent. It remains high throughout childhood and peaks during puberty, when estrogen (in females and also males via aromatization) promotes even higher rates of GH secretion. Thyroid hormone also enhances GH and IGF-I secretion to support bone growth and maturation. Adults continue to produce GH, consistent with its role in metabolism, before levels fall during senescence.


Physiology_Levy

Physiology_Levy. IGFs are multifunctional hormones that regulate cellular proliferation, differentiation, and metabolism. These protein hormones resemble insulin in structure and function. The two hormones in this family, IGF-I and IGF-II, are produced in many tissues and have autocrine, paracrine, and endocrine actions. IGF-I is the major form produced in most adult tissues. IGF-II is the major form produced in the fetus, where it regulates growth of both the fetus and the placenta in a GH-independent manner. Both hormones are structurally similar to proinsulin, with IGF-I exhibiting 42% structural homology with proinsulin. IGFs and insulin show receptor cross-reactivity; IGFs in high concentration mimic the metabolic actions of insulin. Both IGF-I and IGF-II act through type I IGF receptors, which are similar to insulin and epidermal growth factor (EGF) receptors and contain intrinsic tyrosine kinase activity. However, IGF-II also binds to the type II IGF/mannose-6-phosphate receptor. This receptor


Physiology_Levy

Physiology_Levy. to insulin and epidermal growth factor (EGF) receptors and contain intrinsic tyrosine kinase activity. However, IGF-II also binds to the type II IGF/mannose-6-phosphate receptor. This receptor does not resemble the insulin receptor, does not have intrinsic tyrosine kinase activity, and probably functions to limit IGF-II signaling through the type I receptor. IGFs stimulate glucose and amino acid uptake and protein and DNA synthesis. They were initially called somatomedins because of their growth-mediating actions on cartilage, bone, and other organs. It was originally proposed that IGF-I is produced exclusively in the liver upon GH stimulation. During puberty, when GH levels increase (


Physiology_Levy

Physiology_Levy. Fig. 41.19 ), IGF-I levels increase in parallel. However, it is now known that IGFs are produced in many extrahepatic tissues, exhibiting both autocrine and paracrine actions. Some of these are under the control of GH, whereas others are not. In bone, for example, IGF-I has both endocrine and paracrine effects on linear growth, some of which are GH independent. Hormones such as parathyroid hormone (PTH) and estradiol are also effective stimuli for IGF-I production by osteoblasts. At the same time, GH exerts stimulatory effects on the growth plate that are independent of IGF-I. The liver appears to be the predominant source of the circulating pool of IGF-I (see Fig. 41.19 •Fig. 41.18 LifetimepatternofGHsecretion.GHlevelsarehigherinchildrenthaninadults,withapeakperiodduringpuberty.GHsecretiondeclineswithaging.


Physiology_Levy

Physiology_Levy. Fig. 41.19 •Fig. 41.18 LifetimepatternofGHsecretion.GHlevelsarehigherinchildrenthaninadults,withapeakperiodduringpuberty.GHsecretiondeclineswithaging. Essentially all circulating IGFs are transported in serum bound to IGF binding proteins (IGFBP). IGFBP-3 binds to IGF then associates with another protein called the acid labile subunit (ALS) (see Fig. 41.19 ). GH stimulates hepatic production of IGF-I, IGFBP-3, and ALS. The IGFBP-3/ALS/IGF-I complex mediates transport and bioavailability of IGF-I. Although IGFBPs generally inhibit IGF action, they greatly increase the biological half-life of IGFs (up to 12 hours). IGFBP proteases degrade IGFBP and play a role in locally generating free (i.e., active) IGFs. This is of interest in the context of IGF-responsive cancers (e.g., prostate cancer), which may overexpress one or more IGFBP proteases.


Physiology_Levy

Physiology_Levy. GH plays a dual role in metabolism that is highly dependent on physiological context. At the risk of oversimplification, its dual roles are to: (1) promote growth and protein anabolism when nutritional status is favorable, and (2) switch fuel consumption to lipids, sparing glucose in the fasted state. •Fig. 41.19 RelationshipofGHandIGF-I.GHhasdirectendocrineactionsongrowthandstimulatestheproductionofIGF-I,IGFBP-3andALSintheliver.CirculatingIGF-Iexertsendocrineactionsontargetorgans.IGF-1isalsoproducedlocallyinbone,whereitexertsparacrineeffects.Part,butnotallofthislocalIGF-IproductionisGH-dependent. GH acts through a specific GH receptor (GHR) that is a member of the cytokine receptor family. A GHR dimer binds to GH, which triggers activation of the JAK/STAT signaling pathway (see


Physiology_Levy

Physiology_Levy. GH acts through a specific GH receptor (GHR) that is a member of the cytokine receptor family. A GHR dimer binds to GH, which triggers activation of the JAK/STAT signaling pathway (see Fig. 41.17 ). This results in phosphorylation of STAT5b, which translocates to the nucleus to stimulate transcription of GH-responsive genes. Additional signaling pathways activated by GH include MAPK and PI3K among others.


Physiology_Levy

Physiology_Levy. In the fed state, GH is a protein anabolic hormone that increases cellular amino acid uptake and incorporation into protein. Consequently it produces nitrogen retention (positive nitrogen balance) and decreases urea production. The muscle wasting that occurs concomitant with aging has been proposed to be caused at least in part by the decrease in GH secretion that occurs during senescence. In children, GH increases skeletal, muscular, and visceral growth; children without GH show growth stunting or dwarfism. GH promotes cartilage growth and both linear and appositional growth of long bones ( Fig. 41.20 , green arrowheads). Although GH is an effective stimulator of IGF production, this response requires insulin, which supports GH receptor expression and signaling in hepatocytes. When a balanced supply of nutrients is available, high serum glucose levels stimulate insulin secretion and high serum amino acid levels promote GH secretion (


Physiology_Levy

Physiology_Levy. Fig. 41.21, top ). These conditions are appropriate for growth, and GH in turn stimulates IGF-I production by the liver. IGFs are mitogenic and have profound anabolic effects on many organs and tissues, including muscle, cartilage, and bone. Together, GH and IGF-I promote chondrocyte proliferation, differentiation, and hypertrophy during the process of endochondral ossification (see Fig. 41.20, green arrowheads). After closure of the epiphyses, longitudinal growth ceases but appositional growth of long bones continues. IGF-I stimulates osteoblast replication and synthesis of collagen and bone matrix. Not surprisingly, serum IGF levels correlate well with growth in children. The role of GH changes with alteration of nutritional status. If the diet is high in calories but low in amino acids, for example, high carbohydrate availability promotes insulin secretion but low serum amino acid levels inhibit GH and IGF production (see


Physiology_Levy

Physiology_Levy. Fig. 41.21, middle). These responses allow dietary carbohydrates and fats to be stored, but conditions are unfavorable for growth. In the fasted state, on the other hand, when nutrient availability wanes, serum GH levels rise and serum insulin levels fall in response to hypoglycemia (see


Physiology_Levy

Physiology_Levy. Fig. 41.21, bottom). In the absence of insulin, peripheral glucose utilization decreases, thereby conserving glucose for essential tissues such as the brain. In these circumstances the rise in 750 SECTION8Berne & Levy Physiology •Fig. 41.20 BiologicaleffectsofGHandIGF-I.Anabolicgrowth-promotingeffectsthatoccurwhennutritionalstatusisfavorableareindicatedbygreenarrowheads.MetaboliceffectsofGHthatmobilizefatwhilesparingglucoseandproteinduringfastingaredenotedbyredarrowheads.IGFBP,insulinlikegrowthfactor–bindingprotein.Adipose tissue GH Liver Muscle ˜ Lean body mass ˛ Adiposity ˛ Glucose uptake ˜ Lipolysis ˜ RNA synthesis ˜ Protein synthesis ˜ Gluconeogenesis ˜ IGFBP ˜ IGFs ˛ Glucose uptake ˜ Amino acid uptake ˜ Protein synthesis IGF-I fed state fasted state Kidney Pancreas Intestine Islets Parathyroids Skin Connective tissue Bone, heart, lung ˜ Protein synthesis ˜ RNA synthesis ˜ DNA synthesis ˜ Cell size and number ˜ Amino acid uptake ˜ Protein synthesis ˜ RNA synthesis ˜ DNA synthesis


Physiology_Levy

Physiology_Levy. Skin Connective tissue Bone, heart, lung ˜ Protein synthesis ˜ RNA synthesis ˜ DNA synthesis ˜ Cell size and number ˜ Amino acid uptake ˜ Protein synthesis ˜ RNA synthesis ˜ DNA synthesis ˜ Collagen ˜ Chondroitin sulfate ˜ Cell size and number ˜ Linear growth Chondrocytes ˜ Organ size ˜ Organ function ˜ Caloric mobilization (e.g., lipids) •Fig. 41.21 DifferentialregulationofGH,insulin,andIGF-Isecretioncoordinatesavailabilityofnutrientswithgrowthandproteinanabolism,caloricstorage,orcaloricmobilization(primarilylipids).


Physiology_Levy

Physiology_Levy. GH secretion is beneficial because it shifts metabolism to lipid as an energy source, thereby conserving carbohydrate and protein. This involves coordinated direct actions of GH on the liver, muscle, and adipose tissue (see Fig. 41.20 , red arrowheads).


Physiology_Levy

Physiology_Levy. GH is a lipolytic hormone. In adipocytes it mobilizes fatty acids and glycerol from triacylglycerol by combined direct and indirect activation of adipocyte lipases. An important indirect action of GH is sensitization of adipocytes to the lipolytic actions of catecholamines, which are also elevated during fasting. Serum fatty acid levels rise as a result of GH action, and more fats are used for energy production. Fatty acid uptake and β-oxidation increase in skeletal muscle and liver. GH can be ketogenic as a result of the increase in fatty acid oxidation when insulin is absent. GH also alters carbohydrate metabolism, causing blood glucose levels to rise. Many of its actions may be secondary to increased fat mobilization and oxidation. For example, an increase in serum free fatty acids inhibits uptake of glucose in skeletal muscle and adipose tissue. The hyperglycemic effects of GH are mild and slower than those of glucagon and epinephrine. Liver glucose output increases, but this is


Physiology_Levy

Physiology_Levy. uptake of glucose in skeletal muscle and adipose tissue. The hyperglycemic effects of GH are mild and slower than those of glucagon and epinephrine. Liver glucose output increases, but this is not an effect of GH on glycogenolysis. The increase in fatty acid oxidation and hence the rise in liver acetyl CoA stimulate gluconeogenesis. GH also directly stimulates expression of the gluconeogenic enzyme PEPCK through activation of STAT5b. These actions increase glucose production by the liver from substrates such as lactate and glycerol. The latter is released into the circulation as a result of GH-induced lipolysis in adipocytes.


Physiology_Levy

Physiology_Levy. GH antagonizes the action of insulin at the postreceptor level in skeletal muscle and adipose tissue (but not the liver). Hypophysectomy (removal of the pituitary gland) can improve diabetic management because GH, like cortisol, decreases insulin sensitivity. Because GH produces insulin insensitivity, it is considered a diabetogenic hormone. Therefore when secreted in excess (e.g., in acromegaly), GH can cause diabetes mellitus, and the insulin levels necessary to maintain normal metabolism increase. Excessive insulin secretion resulting from an excess of GH can cause damage to pancreatic beta cells. In the absence of GH, insulin secretion declines. Thus normal levels of GH are required for normal pancreatic function and insulin secretion.


Physiology_Levy

Physiology_Levy. GH deficiency in adults is becoming recognized as a pathological syndrome. If GH deficiency occurs after the epiphyses close, growth is not impaired. GH deficiency is one of many possible causes of hypoglycemia. Recent studies have shown that extended deficiencies of GH lead to changes in body composition. Fat as a percentage of body weight increases, whereas lean body mass declines. In addition, muscle weakness and early exhaustion are symptoms of GH deficiency. There has been interest in using GH in elderly populations to reverse age-related physical decline and body composition, but studies to date have shown small changes in body composition, no functional benefits, and increased risk of adverse events.


Physiology_Levy


Physiology_Levy

Physiology_Levy. The Lactotrope The lactotrope produces the hormone prolactin, which is a 199–amino acid single-chain protein. PRL is structurally related to GH and hPL (see ). Like GH, the PRL receptor is a member of the cytokine family coupled to the JAK/STAT signaling pathways. Because the primary action of PRL in humans is related to breast development and function during pregnancy and lactation, the regulation and actions of prolactin will be discussed in detail in In the context of the pituitary gland, it should be appreciated that the lactotrope differs from the other endocrine cell types of the adenohypophysis in two major ways: 1. The lactotrope is not part of an endocrine axis. This means PRL acts directly on nonendocrine cells (primarily of the breast) to induce physiological changes. 2.


Physiology_Levy

Physiology_Levy. 2. Production and secretion of PRL are predominantly under inhibitory control by the hypothalamus. Thus disruption of the pituitary stalk and the hypothalamohypophyseal portal vessels (e.g., secondary to surgery or physical trauma) results in an increase in PRL levels but a decrease in ACTH, TSH, FSH, LH, and GH. PRL circulates unbound to serum proteins and thus has a relatively short half-life of about 20 minutes. Normal basal serum concentrations are similar in men and women. Release of PRL is normally under tonic inhibition by the hypothalamus. This is exerted by dopaminergic tracts that secrete dopamine in the median eminence. There is also evidence for existence of a prolactin-releasing factor (PRF). The exact nature of this compound is not known, although many factors, including TRH and hormones in the glucagon family (secretin, glucagon, VIP, and gastric inhibitory polypeptide [GIP]) can stimulate release of PRL.


Physiology_Levy

Physiology_Levy. PRL is one of the many hormones released in response to stress. Surgery, fear, stimuli causing arousal, and exercise are Upon completion of this chapter the student should be able to answer the following questions: 1. Describe the anatomy and histology of the thyroid gland, including the structure of the thyroid follicle. 2. Explain how thyroid hormones are synthesized within the thyroid gland, including the processes of iodine uptake, iodination of tyrosine residues in thyroglobulin by thyroid peroxidase/dual oxidase, and coupling to form T4 and T3. 3. Describe the process of endocytosis by which thyroglobulin is retrieved from the follicle lumen and processed to yield T3 and T4, which are secreted into the circulation. 4. Diagram the hypothalamic-pituitary-thyroid axis to show how TSH regulates thyroid function and how thyroid hormones feed back to regulate the axis. List examples of how central input can alter the set point of the axis. 5.


Physiology_Levy

Physiology_Levy. 5. Discuss the role of thyroid-binding proteins in the transport and stability of thyroid hormones, and the role of peripheral deiodinases in the activation of T4 to T3 or inactivation to reverse T3. Contrast the cellular location and function of the D1 and D2 deiodinases. 6. Describe the mechanisms of thyroid hormone action, including the nature and location of the thyroid hormone receptor and its ability to either repress or activate target gene transcription. 7. Discuss the actions of thyroid hormone during development, especially on the central nervous system (CNS) and skeleton, including the consequences of severe hypothyroidism. 8. Describe the effects of thyroid hormone on basal metabolic rate and thermogenesis, on the cardiovascular system (heart rate, cardiac output, systemic vascular resistance), and on other organ systems (skin, skeletal muscle, digestive tract).


Physiology_Levy

Physiology_Levy. he thyroid gland produces the prohormone tetraiodothyronine (T4, also called thyroxine) and the active hormone triiodothyronine (T3). Synthesis of T4 and T3 requires iodine, which can be a limiting factor in some parts of the world. Much of T3 is also made by peripheral conversion of T4 to T3. Thyroid hormone acts primarily through a nuclear receptor that regulates gene transcription. T3 is critical for normal brain and bone development and has broad effects on metabolism and cardiovascular function in adults. Anatomy and Histology of the Thyroid Gland The thyroid gland is composed of right and left lobes that sit anterolateral to the trachea ( Fig. 42.1). Typically the two lobes are connected by a midventral isthmus. The thyroid gland receives a rich blood supply. It is drained by three sets of veins on each side: the superior, middle, and inferior thyroid veins. The thyroid gland receives sympathetic innervation that is vasomotor but not secretomotor.


Physiology_Levy

Physiology_Levy. The functional unit of the thyroid gland is the thyroid follicle, a spherical structure about 200 to 300 µm in diameter that is surrounded by a single layer of thyroid epithelial cells ( Fig. 42.2 ). The epithelium sits on a basal lamina, the outermost structure of the follicle, and is surrounded by a rich capillary supply. The apical side of the follicular epithelium faces the lumen of the follicle. The follicular lumen itself is filled with colloid, which is composed of thyroglobulin. This large (660 kDa) protein is secreted into the lumen and iodinated by the thyroid epithelial cells, serving as a scaffold for production of thyroid hormones. The size of the epithelial cells and the amount of colloid are dynamic features that change with activity of the gland. The thyroid gland contains another type of cell in addition to follicular cells. Scattered within the gland are parafollicular cells, or C cells, which are the source of the polypeptide hormone calcitonin (see


Physiology_Levy

Physiology_Levy. Production of Thyroid Hormones The secretory products of the thyroid gland are iodothyronines ( Fig. 42.3 ), a class of hormones formed by the coupling of two iodinated tyrosine molecules. Approximately 90% of the thyroid output is 3,5,3′,5′-tetraiodothyronine (thyroxine, or T4). T4 is primarily a prohormone. About 10% is 3,5,3′-triiodothyronine (T3), which is the active form of thyroid hormone. Less than 1% of thyroid output is 3,3′,5′-triiodothyronine (reverse T3, or rT3), which is inactive. Normally these three products are secreted in the same proportions at which they are stored in the gland. Because the primary product of the thyroid gland is T4, yet the active form of thyroid hormone is T3, the thyroid axis relies heavily on peripheral conversion through the action of thyronine-specific deiodinases (see


Physiology_Levy

Physiology_Levy. Fig. 42.3 ). Most • Fig. 42.1 A and B, Anatomy of the thyroid gland. C, Image of pertechnetate uptake by a normal thyroid gland. (Modified from Drake RL et al. Gray’s Anatomy for Students. Philadelphia: Churchill Livingstone; 2005.) conversion of T4 to T3 by type 1 deiodinase (D1) occurs in tissues with high blood flow and rapid exchange with plasma, such as the liver and kidneys. This process supplies basal circulating T3 for uptake by other tissues in which local T3 generation is low or absent. D1 is also expressed in the thyroid (again, where T4 is abundant) and has relatively low affinity (i.e., a Km of 1 µM) for T4. Levels of D1 are paradoxically increased in hyperthyroidism and contribute to the elevated circulating T3 levels in this disease.


Physiology_Levy

Physiology_Levy. The brain maintains constant intracellular levels of T3 by a high-affinity deiodinase called type 2 deiodinase (D2) that is expressed in glial cells of the CNS. D2 has a Km of 1 nM and maintains intracellular concentrations of T3 even when circulating T4 falls to low levels. D2 is also present in pituitary thyrotropes. There, D2 acts as a “thyroid axis sensor” that mediates the ability of circulating T4 to feed back on secretion of thyroid stimulating hormone (TSH). Expression of D2 is increased during hypothyroidism, which helps maintain constant T3 levels in the brain. There is also an “inactivating” deiodinase called type 3 deiodinase (D3). D3 is a high-affinity inner ring deiodinase that converts T4 to the inactive rT3. Type 3 deiodinase is increased during hyperthyroidism, which helps blunt overproduction of T4. All forms of iodothyronines are eventually further deiodinated to noniodinated thyronine.


Physiology_Levy

Physiology_Levy. Because iodide plays a unique role in thyroid physiology, a description of thyroid hormone synthesis requires some understanding of iodide turnover (


Physiology_Levy

Physiology_Levy. Fig. 42.4 ). An average of 400 µg of iodide per person is ingested daily in the United States, versus a minimum daily requirement of 150 µg for adults, 90 to 120 µg for children, and 200 µg for pregnant women. In the steady state, the same amount, 400 µg, is excreted in urine. Iodide is actively concentrated in the thyroid gland, salivary glands, gastric glands, lacrimal glands, mammary glands, and choroid plexus. About 70 to 80 µg of iodide is taken up daily by the thyroid gland from a circulating pool that contains approximately 250 to 750 µg of iodide. The total iodide content of the thyroid gland averages 7500 µg, virtually all of which is in the form of stored iodothyronine in colloid thyroglobulin. In the steady state, 70 to 80 µg of iodide, or about 1% of the total, is released from the gland daily. Of this amount, 75% is secreted as thyroid hormone and the remainder as free iodide. The large ratio (100:1) of iodide stored in the form of hormone to the amount turned over daily


Physiology_Levy

Physiology_Levy. the gland daily. Of this amount, 75% is secreted as thyroid hormone and the remainder as free iodide. The large ratio (100:1) of iodide stored in the form of hormone to the amount turned over daily protects against iodide deficiency for about 2 months. Iodide is also conserved by a marked reduction in renal excretion of iodide as its concentration in serum falls.


Physiology_Levy

Physiology_Levy. •Fig. 42.2 Histologyofthethyroidglandatlow(upper panel) andhigh(lower panel) magnification.C,colloid;F,thyroidfollicles;S,connectivetissuesepta.(FromYoungBetal.Wheater’s Functional Histology. 5thed.Philadelphia:ChurchillLivingstone;2006.) CHAPTER 42 The Thyroid Gland Overview of Thyroid Hormone Synthesis To understand thyroid hormone synthesis and secretion, one must appreciate the directionality of each process as it relates to the polarized thyroid epithelial cell ( Fig. 42.5 ). Synthesis of thyroid hormone requires two precursors: iodide and thyroglobulin. Iodide is transported across cells from the basal (vascular) side to the apical (follicular luminal) side of the thyroid epithelium. Thyroglobulin is synthesized and secreted across the apical membrane into the follicular lumen. Thus synthesis involves a basal-to-apical movement of these precursors into the follicular lumen (see


Physiology_Levy

Physiology_Levy. Fig. 42.5 ). Actual synthesis of iodothyronines occurs enzymatically within the follicular lumen close to the apical membrane of the epithelial cells (see Synthesis of Iodothyronines on ). Secretion of thyroid hormone involves endocytosis of iodinated thyroglobulin and apicalto-basal movement of the endocytotic vesicles, which fuse with lysosomes. Thyroglobulin is enzymatically degraded by lysosomal enzymes, resulting in release of thyroid hormones from the thyroglobulin backbone. Finally, thyroid hormones move across the basolateral membrane, probably through a specific transporter, and ultimately into the blood. Thus secretion involves apical-to-basal movement (see Fig. 42.5 Synthesis of Iodothyronines on a Thyroglobulin Backbone Iodide is actively transported into the gland against chemical and electrical gradients by a sodium-iodide symporter (NIS) located in the basolateral membrane of thyroid epithelial cells (see


Physiology_Levy

Physiology_Levy. Iodide is actively transported into the gland against chemical and electrical gradients by a sodium-iodide symporter (NIS) located in the basolateral membrane of thyroid epithelial cells (see Fig. 42.5 ). NIS is highly expressed in the thyroid gland, but it is also expressed at lower levels in the placenta, salivary glands, and actively lactating breast. One iodide ion is transported uphill against an iodide gradient while two sodium ions move down their electrochemical gradient from extracellular fluid into the thyroid cell. The driving force for this secondary active transporter is provided by plasma membrane Na+,K+-ATPase. Expression of the NIS gene is inhibited by iodide and stimulated by TSH. A reduction in dietary iodide intake depletes the circulating iodide pool and greatly enhances the activity of the iodide trap. When dietary iodide intake is low, the percentage of thyroid uptake of iodide can reach 80% to 90%. The steps in thyroid hormone synthesis are shown in


Physiology_Levy

Physiology_Levy. The steps in thyroid hormone synthesis are shown in Fig. 42.6 . After entering the gland, iodide rapidly moves to the apical plasma membrane of epithelial cells. From there, iodide is transported into the lumen of the follicles by a sodium-independent iodide/chloride transporter called pendrin. Iodide is immediately oxidized and incorporated into tyrosine residues within thyroglobulin (see Fig. 42.5 ). A single iodination forms a monoiodotyrosine (MIT); a second iodination of the same residue produces diiodotyrosine (DIT) (see Fig. 42.6 ). After iodination, two DIT molecules are coupled to form T4; one MIT and one DIT are coupled to form T3. Coupling occurs between iodinated tyrosines that remain part of the primary structure of


Physiology_Levy

Physiology_Levy. I I 3,5,3¢ 5¢ -Tetraiodothyronine (thyroxine, or T4) NH2 HO O CH2CHCOOH Outer ring deiodination (activation) Inner ring deiodination Deiodinases type 1 and 2 I I Deiodinases type 3 I 3,5,3¢ -Triiodothyronine (T3) I NH2 CH2CHCOOHO (inactivation) I I 3,3¢ 5¢ -Triiodothyronine (reverse T3) NH2 CH2CHCOOHHO O •Fig. 42.3 StructureoftheiodothyroninesT4,T3,andreverseT3. •Fig. 42.4 Iodinedistributionandturnoverinhumans.HI,hormone-associatediodine.Stool 10 µg HIUrine 390 µg ITissues Thyroid Extracellular fluid 10 µg HI60 µg HI80 µg I400 µg IDiet 320 µg I20 µg I50 µg I thyroglobulin. This entire sequence of reactions is catalyzed by thyroid peroxidase (TPO), an enzyme complex that spans the apical membrane. The immediate oxidant (electron acceptor) for the reaction is hydrogen peroxide (H2O2). Generation of H2O2 in the follicular lumen is catalyzed by dual oxidases (DUOX1, DUOX2) that are also localized in the apical plasma membrane.


Physiology_Levy

Physiology_Levy. When iodide availability is restricted, formation of T3 is favored. Because T3 is three times as potent as T4, this response provides more active hormone per molecule of organified iodide. The proportion of T3 also increases when the thyroid gland is hyperstimulated by TSH or other activators. Secretion of Thyroid Hormones Once thyroglobulin has been iodinated, it is stored in the lumen of the follicle as colloid (see Fig. 42.2 ). Release of T4 and T3 into the bloodstream is initiated by endocytosis of colloid from the follicular lumen by the processes of macroand micropinocytosis. Endocytotic vesicles then fuse with lysosomes and thyroglobulin is degraded ( Fig. 42.7 Fig. 42.5 ). MIT and DIT molecules, which also are released during proteolysis of thyroglobulin, are rapidly deiodinated within the follicular cell by the enzyme iodotyrosine deiodinase (see


Physiology_Levy

Physiology_Levy. 42.7 Fig. 42.5 ). MIT and DIT molecules, which also are released during proteolysis of thyroglobulin, are rapidly deiodinated within the follicular cell by the enzyme iodotyrosine deiodinase (see Fig. 42.5 ). This deiodinase is specific for MIT and DIT and cannot use T4 and T3 as substrates. The iodide is then recycled into synthesis of T4 and T3. Amino acids from the digestion of thyroglobulin reenter the intrathyroidal amino acid pool and can be reused for protein synthesis. Only minor amounts of intact thyroglobulin leave the follicular cell under normal circumstances. Enzymatically released T4 and T3 are transported across the basal side of the cell and enter the blood. •Fig. 42.5 Synthesisandsecretionofthyroidhormonesbythethyroidepithelialcell.


Physiology_Levy

Physiology_Levy. •Fig. 42.5 Synthesisandsecretionofthyroidhormonesbythethyroidepithelialcell. I I I I 3,5,3¢ 5¢ -Tetraiodothyronine (thyroxine, or T4) NH2 CH2CHCOOHHO O I I NH2 CH2CHCOOHHO O I NH2 CH2CHCOOHHO I NH2 CH2CHCOOH + I I DIT DIT NH2 CH2CHCOOH + I I NH2 CH2CHCOOHHO I Diiodotyrosine (DIT) or NH2 CH2CHCOOHHO Monoiodotyrosine (MIT) NH2 CH2CHCOOHHO Tyrosine NH2 CH2CHCOOHI2 + HO DIT MIT 3,5,3¢ -Triiodothyronine (T3) •Fig. 42.6 Reactionsinvolvedinthegenerationofiodide,MIT,DIT,T3,andT4.


Physiology_Levy

Physiology_Levy. DIT MIT 3,5,3¢ -Triiodothyronine (T3) •Fig. 42.6 Reactionsinvolvedinthegenerationofiodide,MIT,DIT,T3,andT4. Transport and Metabolism tissues in addition to exerting negative feedback on the pituitary and hypothalamus. The major binding protein is thyroxine-binding globulin (TBG), which is synthesized Secreted T4 and T3 circulate in the bloodstream almost in the liver and binds one molecule of T4 or T3. About 70% entirely bound to proteins. Normally only about 0.03% of circulating T4 and T3 is bound to TBG; 10% to 15% of total plasma T4 and 0.3% of total plasma T3 exist in is bound to another specific thyroid-binding protein called the free state (


Physiology_Levy

Physiology_Levy. Fig. 42.8 ). Free T3 is biologically active and transthyretin (TTR). Albumin binds 15% to 20%, and mediates the effects of thyroid hormone on peripheral 3% is bound to lipoproteins. Ordinarily only alterations in ).CirculatingthyroidhormonesfeedbackonthepituitaryglandtodecreaseTSHsecretion,primarilybyrepressingTSHβ subunitgeneexpression.Thepituitaryglandexpressesthehigh-affinityD2,whichconvertsT4enteringthesecellstoT3.ThusfeedbackinthyrotropesmediatedbyintracellularT3representsanintegratedmeasureofcirculatingfreeT4andT3(see ).BecausethediurnalvariationinTSHsecretionissmall,thyroidhormonesecretionandplasmaconcentrationsarerelativelyconstant.OnlysmallnocturnalincreasesinsecretionofTSHandreleaseofT4occur.Thyroidhormonesalsofeedbackonhypothalamicthyroid-releasinghormone(TRH)secretingneurons.Intheseneurons,T3inhibitsexpressionoftheprepro-TRHgene.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Thethyroidcanbeimagedwitharectilinearscannerorgammacameraafteradministrationofatracer,123I,131I,ortheiodine-mimicpertechnetate(99mTc).Imagingcandisplaythesizeandshapeofthethyroid(see Fig.42.1C )aswellasheterogeneitiesofactiveversusinactivetissuewithinthethyroidgland.Suchheterogeneitiesareoftenduetothedevelopmentofthyroid nodules, whichareregionsofenlargedfollicleswithevidenceofregressivechangesduetocyclesofstimulationandinvolution.“Hot” nodules (i.e.,nodulesthatdisplayhighRAIUonimaging)arenotusuallycancerousbutmayleadtothyrotoxicosis(hyperthyroidism).“Cold” nodules are10timesmorelikelytobecancerous.Suchnodulescanbesampledforpathologicalanalysisbyfine-needle aspiration biopsy. Thethyroidcanalsobeimagedbyultrasonography, whichissuperiorinresolutiontoRAIUimaging.Ultrasonographyisusedtoguidethephysicianduringfine-needleaspirationbiopsyofanodule.Thehighestresolutionofthethyroidisachievedwithmagnetic resonance imaging (MRI).


Physiology_Levy

Physiology_Levy. A B Colloid in endocytic vesicles Colloid in lumen of thyroid follicle •Fig. 42.7 Before(A)andminutesafter(B)rapidinductionofthy-roglobulinendocytosisbyTSH.(FromWollmanSHetal.J Cell Biol 1964;21:191.) TBG concentration significantly affect total plasma T4 and T3 levels. Two important biological functions have been ascribed to TBG. First, it maintains a large circulating reservoir of T4 that buffers any acute changes in thyroid gland function. Second, binding of plasma T4 and T3 to proteins prevents loss of these relatively small hormone molecules in urine and thereby helps conserve iodide. TTR transports T4 in cerebrospinal fluid and provides thyroid hormones to the CNS. Regulation of Thyroid Function


Physiology_Levy

Physiology_Levy. Regulation of Thyroid Function The most important regulator of thyroid gland function and growth is the hypothalamic-pituitary thyroid releasing •Fig. 42.8 TransportofT4andT3inserumbytransportproteinsandpercentagesofboundandfreehormone.Thyroid secretion Protein-Bound T4 (99.98%) & T3 (99.7%) Thyroid-binding globulin (TBG) Transthyretin (TTR) Albumin • Feedback • Activation to T3 • Inactivation • Excretion • Tissue actions • Feedback • Inactivation • Excretion Free T4 (0.02%) & T3 (0.3%) Total T4 8 µg/dL Total T3 0.14 µg/dL Free T4 1.6 ng/dl Free T3 – 0.42 ng/dl T3 T4 123I Uptake (% of dose) •Fig. 42.9 Thyroidglandiodothyronineuptakedefectiveorganificationstates. ). TSH stimulates every aspect of thyroid function. TSH has immediate, intermediate, and long-term actions on the thyroid epithelium. Rapid actions of TSH include pinocytosis of colloid droplets in the cytoplasm, which represent thyroglobulin within endocytic vesicles (see


Physiology_Levy

Physiology_Levy. Fig. 42.7 ). TSH stimulates the proteolysis of thyroglobulin and release of T4 and T3 from the gland. Iodide uptake and TPO activity increase. TSH also stimulates entry of glucose into the hexose monophosphate shunt pathway, which generates the reduced nicotinamide adenine dinucleotide phosphate (NADPH) needed for the peroxidase reaction. Intermediate effects of TSH on the thyroid gland occur after hours to days and involve protein synthesis and expression of numerous genes, including those encoding NIS, thyroglobulin, and TPO. Sustained TSH stimulation leads to the long-term effects of hypertrophy and hyperplasia of follicular cells. Capillaries proliferate and thyroid blood flow increases. These actions, which underlie the growth-promoting effects of TSH on the gland, are supported by local production of growth factors. A noticeably enlarged thyroid gland is called a goiter (


Physiology_Levy

Physiology_Levy. Fig. 42.10 ). Endemic goiter is due to lack of adequate iodine in the diet, which results in low thyroid hormone and elevated TSH levels. Physiological Effects of Thyroid Hormone Thyroid hormone acts on essentially all cells and tissues, and imbalances in thyroid function constitute some of the most common endocrine diseases. Thyroid hormone has many direct actions, but it also acts in more subtle ways to optimize the actions of several other hormones and neurotransmitters. curvesfornormal,hypothyroid,hyperthyroid,and •Fig. 42.10 Thethyroidglandislocatedintheanterioraspectoftheneck,whereitiseasilyvisualizedwhenenlarged(goiter). ˜ Cardiac muscle Myosin heavy chain ˝/˙ ratio Na+, K+-ATPase Sarcoplasma Ca-ATPase ˙-Adrenergic signaling G-protein stimulatory/ •Fig. 42.11 Mechanismsbywhichthyroidhormoneincreasescardiacoutput.Theindirectmechanismsareprobablyquantitativelymoreimportant.


Physiology_Levy

Physiology_Levy. TheprimaryclinicalstatefoundinGravesdiseaseisthyrotoxicosis—thestateofexcessivethyroidhormoneinbloodandtissues.Apatientwiththyrotoxicosispresentsoneofthemoststrikingpicturesinclinicalmedicine.Thelargeincreaseinmetabolicrateismanifestedasweightlossdespiteincreasedfoodintake.Excessheatproductioncausesdiscomfortinwarmenvironments,sweating,andgreaterintakeofwater.Theincreaseinadrenergicactivityproducesarapidheartrate,hyperkinesis,tremor,nervousness,andawide-eyedstare.Weaknessiscausedbyalossofmusclemassaswellasimpairedmusclefunction.Othersymptomsincludealabileemotionalstate,breathlessnessduringexercise,anddifficultyswallowingorbreathingbecauseofcompressionoftheesophagusortracheabytheenlargedthyroidgland.Themostcommoncardiovascularsignissinustachycardia.There Perhaps the most clinically important actions of thyroid hormone are those on cardiovascular physiology. T3 increases cardiac output, thereby ensuring sufficient O2 delivery to tissues (


Physiology_Levy

Physiology_Levy. Perhaps the most clinically important actions of thyroid hormone are those on cardiovascular physiology. T3 increases cardiac output, thereby ensuring sufficient O2 delivery to tissues ( Fig. 42.11). The resting heart rate and stroke volume are increased. The speed and force of myocardial contractions are enhanced (positive chronotropic and inotropic effects, respectively), and the diastolic relaxation isincreasedcardiacoutputassociatedwithawidenedpulsepressuresecondarytoapositiveinotropiceffectcoupledwithdecreasedsystemicvascularresistance.AmajorclinicalsigninGravesdiseaseisexophthalmos (abnormalprotrusionoftheeyeball)andperiorbital edema. ThisiscausedbyautoantibodybindingtotheTSHreceptorexpressedonorbitalfibrocytes,leadingtoproductionofinflammatorycytokines.


Physiology_Levy

Physiology_Levy. time is shortened (positive lusitropic effect). Systolic blood pressure is modestly augmented and diastolic blood pressure is decreased. The resultant widened pulse pressure reflects the combined effects of the increased stroke volume and the reduction in systemic vascular resistance secondary to blood vessel dilation in skin, muscle, and heart. These effects in turn are partly due to the increase in tissue production of heat and CO2 that thyroid hormone induces (see on Basal Metabolic Rate and Thermogenesis). In addition, however, thyroid hormone decreases systemic resistance by dilating arterioles in the peripheral circulation. Total blood volume is increased by activation of the renin-angiotensinaldosterone axis, thereby increasing renal tubular sodium reabsorption (see The cardiac inotropic effects of T3 are both direct and indirect. The latter are due primarily to enhanced responsiveness to catecholamines (see ). Direct inotropic effects (see


Physiology_Levy

Physiology_Levy. The cardiac inotropic effects of T3 are both direct and indirect. The latter are due primarily to enhanced responsiveness to catecholamines (see ). Direct inotropic effects (see Fig. 42.11 ) involve regulation of multiple proteins that enhance contractility, including increased α-myosin heavy chain expression and inhibition of the plasma membrane Na+/Ca++ exchanger. Sarcoplasmic reticulum Ca++-ATPase (SERCA) is increased by T3, whereas phospholamban is decreased. As a result, sequestration of calcium during diastole is enhanced and the relaxation time is shortened. Increased ryanodine Ca++ channels in the sarcoplasmic reticulum promote release of Ca++ from the sarcoplasmic reticulum during systole.


Physiology_Levy

Physiology_Levy. Increased O2 use ultimately depends on an increased supply of substrates for oxidation. T3 augments glucose absorption from the gastrointestinal tract and increases glucose turnover (glucose uptake, oxidation, and synthesis). In adipose tissue, thyroid hormone induces enzymes for the synthesis of fatty acids, including acetyl-CoA carboxylase and fatty acid synthase, and enhances lipolysis by increasing the number of β-adrenergic receptors (see the Autonomic Nervous System ). Thyroid hormone also enhances the clearance of chylomicrons. Thus lipid turnover (free fatty acid release from adipose tissue and oxidation) is augmented. Protein turnover (release of muscle amino acids, protein degradation, and to a lesser extent protein synthesis and urea formation) is also increased. T3 potentiates the respective stimulatory effects of epinephrine, norepinephrine, glucagon, cortisol, and growth hormone on gluconeogenesis,


Physiology_Levy

Physiology_Levy. CHAPTER 42 The Thyroid Gland lipolysis, ketogenesis, and proteolysis of the labile protein pool. The overall metabolic effect of thyroid hormone has been aptly described as accelerating the physiological response to starvation. In addition, thyroid hormone stimulates synthesis of bile acids from cholesterol and promotes biliary secretion. The net effect is a decrease in the body pool and plasma levels of total and low-density lipoprotein cholesterol. Metabolic clearance of adrenal and gonadal steroid hormones, some B vitamins, and certain administered drugs is also increased by thyroid hormone.


Physiology_Levy

Physiology_Levy. Thyroid hormones stimulate thermogenesis by affecting both adenosine triphosphate (ATP) utilization and the efficiency of ATP synthesis. ATP utilization is enhanced by upregulation of several energy-dependent processes, including Na+,K+-ATPase and SERCA, particularly in skeletal muscle, where calcium cycling between the cytoplasm and sarcoplasmic reticulum uses ATP and generates heat. Recently it has been demonstrated that brown fat in humans, once thought to be important only in neonates, appears to play a role in facultative thermogenesis in adults. Imaging studies have demonstrated the presence of brown fat in the mediastinum, particularly in lean individuals, and metabolic activity in brown fat is enhanced by exposure to cold. Brown fat expresses uncoupling protein-1 (UCP1), also called thermogenin, which causes the proton gradient across the inner mitochondrial membrane to be dissipated as heat, which is then disseminated to the rest of the body by the circulation. UCP1 is


Physiology_Levy

Physiology_Levy. called thermogenin, which causes the proton gradient across the inner mitochondrial membrane to be dissipated as heat, which is then disseminated to the rest of the body by the circulation. UCP1 is regulated by thyroid hormone, and brown fat expresses D2, providing intracellular conversion of T4 to T3. Brown fat thermogenesis involves a synergistic interaction between thyroid hormones and the sympathetic nervous system. Catecholamines promote lipolysis and upregulate expression of D2. T3 in turn upregulates adrenergic receptors and enhances catecholamine responsiveness. Hyperthyroidism is accompanied by heat intolerance, whereas hypothyroidism is accompanied by cold intolerance.


Physiology_Levy

Physiology_Levy. Thyroid hormone stimulates O2 utilization and enhances O2 delivery. Appropriately, T3 increases the resting respiratory rate, minute ventilation, and the ventilatory response to hypercapnia and hypoxia. These actions maintain a normal arterial PO2 when O2 utilization is increased and a normal PCO2 when CO2 production is increased. Additionally the hematocrit increases slightly to enhance O2-carrying capacity. This increase results from stimulation of erythropoietin production by the kidney. Normal function of skeletal muscles also requires optimal amounts of thyroid hormone. This requirement may be related to regulation of energy production and storage. Glycolysis and glycogenolysis are increased, whereas glycogen and creatine phosphate are reduced by thyroid hormone excess. The inability of muscle to take up and phosphorylate creatine leads to its increased urinary excretion. Effects on the Autonomic Nervous System and Catecholamine Action


Physiology_Levy

Physiology_Levy. Effects on the Autonomic Nervous System and Catecholamine Action As already mentioned, there is important synergism between catecholamines and thyroid hormones. Thyroid hormones are synergistic with catecholamines in increasing the metabolic rate, heat production, heart rate, motor activity, and excitation of the CNS. T3 may enhance sympathetic nervous system activity by increasing the number of β-adrenergic receptors in heart muscle and the generation of intracellular second messengers such as cyclic adenosine monophosphate (cAMP).


Physiology_Levy

Physiology_Levy. A major effect of thyroid hormone is to promote growth and maturation. A small but crucial amount of thyroid hormone crosses the placenta, and the fetal thyroid axis becomes functional at midgestation. Thyroid hormone is extremely important for normal neurological development and proper bone formation in the fetus. In infants, insufficient fetal thyroid hormone causes congenital hypothyroidism, characterized by irreversible intellectual disability and short stature (see In the Clinic box). Effects on Bone, Hard Tissue, and Dermis Thyroid hormone promotes endochondral ossification, linear bone growth, and maturation of the epiphyseal bone centers. T3 enhances maturation and activity of chondrocytes in the cartilage growth plate, in part by increasing local growth factor production and action. During linear postnatal growth, T3 supports the actions of growth hormone, insulinlike growth factor (IGF)-I, and other growth factors. T3 also supports normal adult bone remodeling.


Physiology_Levy

Physiology_Levy. The progression of tooth development and eruption depends on thyroid hormone, as does the normal cycle of growth and maturation of the epidermis, its hair follicles, and nails. The normal degradative processes in these structural and integumentary tissues are stimulated by thyroid hormone. Thus either too much or too little thyroid hormone can lead to hair loss and abnormal nail formation. Thyroid hormone regulates the structure of subcutaneous tissue by inhibiting synthesis and increasing degradation of mucopolysaccharides (glycosaminoglycans) and fibronectin in the extracellular connective tissue (see later description of myxedema). Effects on the Nervous System


Physiology_Levy

Physiology_Levy. Effects on the Nervous System Thyroid hormone regulates the timing and pace of development of the CNS. Thyroid hormone deficiency in utero and in early infancy inhibits growth of the cerebral and cerebellar cortex, proliferation of axons and branching of dendrites, synaptogenesis, myelination, and cell migration. Irreversible CNS impairment results when neonatal thyroid hormone deficiency is not recognized and treated promptly. These morphological defects are paralleled by biochemical abnormalities. Decreased thyroid hormone levels reduce cell size, RNA and protein content, tubulinand microtubuleassociated protein, protein and lipid content of myelin, local production of critical growth factors, and rates of protein synthesis.


Physiology_Levy

Physiology_Levy. Thyroid hormone also enhances wakefulness, alertness, responsiveness to various stimuli, auditory sense, awareness of hunger, memory, and learning capacity. In addition, normal emotional tone depends on proper thyroid hormone availability. Furthermore the speed and amplitude of peripheral nerve reflexes are increased by thyroid hormone, as is motility of the gastrointestinal tract. In both women and men, thyroid hormone plays an important permissive role in regulation of reproductive function. The normal ovarian cycle of follicular development, maturation, and ovulation, the homologous testicular process of spermatogenesis, and maintenance of the healthy pregnant state are all disrupted by significant deviations in thyroid hormone levels from the normal range. In part these deleterious effects may be caused by alterations in the metabolism or availability of steroid hormones. For example, thyroid hormone stimulates hepatic synthesis and release of sex steroid–binding globulin.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Assessment of Skeletal Maturity and Prediction of Adult Height (TW2 Method). NewYork:AcademicPress;1975.C,FromAndersenHJ.In:GardnerLI[ed].Endocrine and Genetic Diseases of Childhood and Adolescence. Philadelphia:Saunders;1975.) hypothyroidismaremutationsingenesinvolvedinthyroidhormoneproduction(e.g.NIS,TPO,thyroglobulin,pendrin)orblockingantibodiestotheTSHreceptor.Theseverityoftheneurologicalandskeletaldefectsiscloselylinkedtothetimingofdiagnosisandthyroidhormone(T4)replacement,withearlytreatmentresultinginanormalcognitiveabilityandsubtleneurologicaldeficits.Ontheotherhand,ifhypothyroidismatbirthremainsuntreatedforonly2to4weeks,theCNSwillnotmaturenormallyinthefirstyearoflife.Developmentalmilestonessuchassitting,standing,andwalkingwillbelate,andsevereirreversiblecognitivedeficitscanresult.Hypothyroidbabiesusuallyappearnormalatbirthbecauseofprotectionbymaternalthyroidhormones.Neonatal screening


Physiology_Levy

Physiology_Levy. screening (T4andTSHlevels)hasthereforeplayedacriticalroleindiagnosisandpreventionofcongenitalhypothyroidism.


Physiology_Levy

Physiology_Levy. Chapter40).Kidneysize, renalplasmaflow,glomerularfiltrationrate,andtransportratesforanumberofsubstancesarealsoincreasedbythyroidhormone. Non-thyroidal illness syndrome (NTIS), also known as euthyroid sick syndrome, occurs frequently in severely ill patients who require hospitalization. NTIS is characterized by decreased levels of both circulating thyroid hormone and TSH caused by CNS-mediated suppression of the hypothalamic-pituitary-thyroid axis. In addition, peripheral metabolism of T4 to inactive rT3 is also increased. A similar pattern is seen upon prolonged fasting. Although it remains incompletely understood, NTIS has been proposed to represent a physiological energy-sparing adaptation to chronic illness or starvation. Mechanism of Thyroid Hormone Action


Physiology_Levy

Physiology_Levy. Mechanism of Thyroid Hormone Action Formanyyearsitwasthoughtthatthyroidhormonesdiffusepassivelyacrosscellmembranes,butthisisnowknowntorequiretransportproteins.TheseincludethemonocarboxylatetransportersMCT8andMCT10,whicharecapableoftransportingbothT4andT3acrosstheplasmamembrane( Fig. 42.13 Fig.42.5 ).Recently,mutationsinMCT8havebeenshowntocauseanX-linkeddevelopmentalsyndromeinhumanscharacterizedbyelevatedT3levels,musclehypoplasia,andsevereneurologicalimpairment.Anothertransporter,OATP1C1,appearstoplayaroleintransportofT4acrosstheblood-brainbarrier.


Physiology_Levy

Physiology_Levy. subunitTSHgeneinpituitarythyrotropes.Thusthenegative-feedbackeffectsofthyroidhormoneonbothTRHandTSHsecretionarelargelymediatedbyTRβ2.


Physiology_Levy

Physiology_Levy. ThereisemergingevidencefornongenomicactionsofT3andT4thataremediatedbyreceptorsactingintheplasmamembrane,mitochondria,orcytoplasm.Insomecasesthesearemodifiedversionsofthenuclearthyroidreceptors.Forexample,truncatedisoformsofTRα1havebeenreportedthatbindT3intheplasmamembranetomediatenongenomiceffectsinboneorthatbindT4inthecytoplasmtoregulatemicrofilamentorganization.Ithasalsobeenreportedthatanintegrin,αvβ3,canactasaT4receptoratthecellsurfacetoregulatecellularproliferationandangiogenesisbyanongenomicmechanism.Theinterplaybetweentheclassicalgenomicandnongenomicactionsofthyroidhormonesislikelytobeanotheractiveareaoffutureresearch. 1. The thyroid gland is situated in the ventral aspect of the neck and is composed of right and left lobes anterolateral to the trachea and connected by an isthmus. 2. The thyroid gland is the source of tetraiodothyronine (thyroxine, T4) and triiodothyronine (T3). 3.


Physiology_Levy

Physiology_Levy. 2. The thyroid gland is the source of tetraiodothyronine (thyroxine, T4) and triiodothyronine (T3). 3. The basic endocrine unit in the gland is a follicle that consists of a single spherical layer of epithelial cells surrounding a central lumen that contains colloid or stored hormone. 4. Iodide is taken up into thyroid cells by a sodium-iodide symporter in the basolateral plasma membrane. 5. T4 and T3 are synthesized from tyrosine and iodide by the enzyme complex of dual oxidase and thyroid peroxidase. Tyrosine residues in thyroglobulin undergo iodination, after which two iodotyrosine molecules are coupled to yield the iodothyronines. 6. Secretion of stored T4 and T3 requires retrieval of thyroglobulin from the follicle lumen by endocytosis. Thyroglobulin is then degraded in endolysosomes to liberate T4 and T3. Iodide is conserved by recycling any iodotyrosine molecules that did not undergo coupling within thyroglobulin. 7.


Physiology_Levy

Physiology_Levy. 7. TSH acts on the thyroid gland via its plasma membrane receptor to stimulate all steps in the production of T4 and T3. These steps include iodide uptake, iodination and coupling, and retrieval from thyroglobulin. TSH also stimulates glucose oxidation, protein synthesis, and growth of epithelial cells. 8. More than 99.5% of T4 and T3 circulates bound to the following proteins: thyroid-binding globulin, Bernal J, et al. Thyroid hormone transporters–functions and clinical implications. Nat Rev Endocrinol. 2015;11:406-417. Bianco AC. Minireview: cracking the metabolic code for thyroid hormone signaling. Endocrinology. 2011;152:3306-3311. transthyretin, and albumin. Only the free fractions of T4 and T3 are biologically active. 9.


Physiology_Levy

Physiology_Levy. transthyretin, and albumin. Only the free fractions of T4 and T3 are biologically active. 9. T4 functions largely as a prohormone whose disposition is regulated by three types of deiodinases. Monodeiodination of the outer ring yields 75% of the daily production of T3, which is the principal active hormone. Alternatively, monodeiodination of the inner ring yields reverse T3, which is biologically inactive. Proportioning of T4 between T3 and reverse T3 regulates the availability of active thyroid hormone. 10. Thyroid hormone is a major positive regulator of the basal metabolic rate and thermogenesis. Other important actions of thyroid hormone are increased heart rate, cardiac output, and ventilation and decreased systemic vascular resistance. Substrate mobilization and disposal of metabolic products are enhanced. 11.


Physiology_Levy

Physiology_Levy. 11. Thyroid hormone action on the CNS and skeleton are crucial for normal growth and development. Absence of the hormone causes congenital hypothyroidism, characterized by poor brain development, short stature, and immature skeletal development. In adults, thyroid hormone supports bone remodeling and degradation of skin and hair. 12. T3 binds to thyroid hormone receptor subtypes responsible for the various actions of thyroid hormone. The thyroid hormone receptor heterodimerizes with RXR to regulate thyroid response elements on target genes, resulting in induction or repression in the presence or absence of T3, respectively. Brent GA. Mechanisms of thyroid hormone action. J Clin Invest. 2012;122:3035-3043. de Vries EM, et al. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol. 2015;225:R67-R81. Krude H, et al. Treatment of congenital thyroid dysfunction: achievements and challenges. Best Pract Res Clin Endocrinol Metab. 2015;29:399-413.


Physiology_Levy

Physiology_Levy. Krude H, et al. Treatment of congenital thyroid dysfunction: achievements and challenges. Best Pract Res Clin Endocrinol Metab. 2015;29:399-413. Upon completion of this chapter the student should be able to answer the following questions: 1. Describe the anatomy and microscopic anatomy of the adrenal gland, including the chromaffin cells of the adrenal medulla and the three zones of the adrenal cortex. 2. Explain the enzymatic reactions involved in generating norepinephrine and epinephrine and integrate those reactions with the regulation of epinephrine synthesis and secretion by the adrenal medulla. 3. Utilize the specific actions of catecholamines to explain an overall sympathetic response to a stress imposed on the body. 4. Describe the first two common reactions of the steroidogenic pathway, and their subcellular locations, and the function of StAR protein in the first reaction. 5.


Physiology_Levy

Physiology_Levy. 4. Describe the first two common reactions of the steroidogenic pathway, and their subcellular locations, and the function of StAR protein in the first reaction. 5. Compare the steroidogenic pathways within the zona glomerulosa, zona fasciculata, and zona reticularis with respect to common and zona-specific reactions. 6. Describe the mechanism of action of glucocorticoids and mineralocorticoids, including the cross-reactivity of cortisol with the mineralocorticoid receptor, and the mechanism to prevent this. 7. Integrate the multiple actions of cortisol throughout the body to explain the hormone’s role during normal development and physiology, and to describe the multiple aspects of the pathophysiology of Addison’s disease and Cushing’s syndrome. 8.


Physiology_Levy

Physiology_Levy. 8. Map out the hypothalamic-pituitary-adrenal axis, including the “loophole” in the feedback mechanisms that leads to excessive androgen production (e.g., in congenital adrenal hyperplasia) in the face of an enzyme deficiency specific to the zona fasciculata and cortisol synthesis. 9. Review the regulation and actions of aldosterone.


Physiology_Levy

Physiology_Levy. 9. Review the regulation and actions of aldosterone. n adults the adrenal glands emerge as fairly complex endocrine structures that produce two structurally distinct classes of hormones: steroids and catecholamines. The catecholamine hormone epinephrine acts as a rapid responder to stresses such as hypoglycemia and exercise to regulate multiple parameters of physiology, including energy metabolism and cardiac output. Stress is also a major secretagogue of the longer-acting steroid hormone cortisol, which regulates glucose utilization, immune and inflammatory homeostasis, and numerous other processes. In addition the adrenal glands regulate salt and volume homeostasis through the steroid hormone aldosterone. Finally, the adrenal gland secretes large amounts of the androgen precursor dehydroepiandrosterone sulfate (DHEAS), which plays a major role in fetoplacental estrogen synthesis and as a substrate for peripheral androgen synthesis in women.


Physiology_Levy

Physiology_Levy. The adrenal glands are bilateral structures located immediately above the kidneys (ad, near; renal, kidney) ( Fig. 43.1 ). In humans they are also referred to as the suprarenal glands because they sit on the superior pole of each kidney. The adrenal glands are similar to the pituitary in that they are derived from both neuronal tissue and epithelial (or epithelial-like) tissue. The outer portion of the adrenal gland, called the adrenal cortex ( Fig. 43.2 ), develops from mesodermal cells in the vicinity of the superior pole of the developing kidney. These cells form cords of epithelial endocrine cells. The cells of the cortex develop into steroidogenic cells (see ). In adults the adrenal cortex is composed of three zones—the zona glomerulosa, the zona fasciculata, and the zona reticularis—that produce mineralocorticoids, glucocorticoids, and adrenal androgens, respectively (see Fig. 43.2B


Physiology_Levy

Physiology_Levy. Fig. 43.2B Soon after the cortex forms, neural crest–derived cells associated with the sympathetic ganglia, called chromaffin cells, migrate into the cortex and become encapsulated by cortical cells. Thus the chromaffin cells establish the inner portion of the adrenal gland, which is called the adrenal medulla (see Fig. 43.2). The chromaffin cells of the adrenal medulla have the potential to develop into postganglionic sympathetic neurons. They are innervated by cholinergic preganglionic sympathetic neurons and can synthesize the catecholamine neurotransmitter norepinephrine from tyrosine. However, high levels of cortisol that drain into the medulla from the adrenal cortex induce expression of the enzyme phenylethanolamine N-methyl transferase (PNMT), which transfers a methyl group onto norepinephrine to produce the catecholamine hormone epinephrine, the primary hormonal product of the adrenal medulla (see Fig. 43.2B).


Physiology_Levy

Physiology_Levy. Fig. 43.2B). CHAPTER 43 The Adrenal Gland 767 • Fig. 43.1 The adrenal glands sit on the superior poles of the kidneys and receive a rich arterial supply from the inferior, middle, and superior suprarenal arteries. The adrenals are drained by a single suprarenal vein. (Modified from Drake RL et al. Gray’s Anatomy for Students. Philadelphia: Churchill Livingstone; 2005.)


Physiology_Levy

Physiology_Levy. Instead of being secreted near a target organ and acting as neurotransmitters, adrenomedullary catecholamines are secreted into blood and act as hormones. About 80% of the cells of the adrenal medulla secrete epinephrine, and the remaining 20% secrete norepinephrine. Although circulating epinephrine is derived entirely from the adrenal medulla, only about 30% of the circulating norepinephrine comes from the medulla. The remaining 70% is released from postganglionic sympathetic nerve terminals and diffuses into the vascular system. Because the adrenal medulla is not the sole source of catecholamine production, this tissue is not essential for life. Synthesis of Epinephrine The enzymatic steps in epinephrine synthesis are shown in


Physiology_Levy

Physiology_Levy. Synthesis of Epinephrine The enzymatic steps in epinephrine synthesis are shown in Fig. 43.4 . Synthesis begins with transport of the amino acid tyrosine into the chromaffin cell cytoplasm and subsequent hydroxylation of tyrosine by the rate-limiting enzyme tyrosine hydroxylase to produce dihydroxyphenylalanine (DOPA). DOPA is converted to dopamine by a cytoplasmic enzyme, aromatic amino acid decarboxylase, and is then transported into the secretory vesicle (also called the chromaffin granule). Within the granule, all dopamine is completely converted to norepinephrine by the enzyme dopamine β-hydroxylase. In most adrenomedullary cells, essentially all of the norepinephrine diffuses out of the chromaffin granule by facilitated transport and is methylated by the cytoplasmic enzyme PNMT to form epinephrine.


Physiology_Levy

Physiology_Levy. The high local concentration of cortisol in the medulla is maintained by the vascular configuration within the adrenal gland. The outer connective tissue capsule of the adrenal gland is penetrated by a rich arterial supply coming from three main arterial branches: the inferior, middle, and superior suprarenal arteries (see