1625915643-5d53d156c9525bd62bd0d3434ecdc231 (843955), страница 87
Текст из файла (страница 87)
The two adrenal glands (right andleft) consist of an inner medullary and outer cortical layer,which produce catecholamines and steroid hormones, respectively. The adrenal medulla and adrenal cortex are derivedfrom embryologically distinct tissues (ectodermal neural crestand endoderm, respectively), and can functionally be considered distinct organs. As a whole, however, the adrenals aresometimes discussed in terms of their role in the stressresponse, during which both medullary catecholamines andcortical steroids are released; this is a narrow view of the adrenals, though, which actually participate in a wide array ofphysiological processes.ADRENAL GLAND STRUCTUREThe human adrenal cortex consists of three distinct histological layers (Fig. 28.2):■■■The outer zona glomerulosa, which synthesizes mineralocorticoid hormones, mainly aldosterone.The middle zona fasciculata, which produces the glucocorticoid hormone cortisol.The inner zona reticularis, which produces male sexhormones (androgens), mainly dehydroepiandrosterone (DHEA) and androstenedione.The adrenal medulla is found beneath the cortex, at the centerof the gland; it contains chromaffin cells that function aspostganglionic cells of the sympathetic nervous system, secreting mainly epinephrine, and in lesser amounts, norepinephrine into the bloodstream.SYNTHESIS AND REGULATION OF ADRENALCORTICAL STEROID HORMONESThe pathways for biosynthesis of adrenal steroids are depictedin Figure 26.3.
Cholesterol, either produced de novo in theadrenal cortex or transported to the cortex in the form of LDLcholesterol, is the precursor of these products. Although illustrated in Figure 28.3 as a single, complex pathway, only portions of the pathway exist in each of the layers of the cortex.For example, the cells of the zona glomerulosa contain theenzymes involved in synthesis of aldosterone, and cells of thezona fasciculata have the enzymes necessary to producecortisol.The hypothalamic-pituitary-adrenal axis (HPA axis) (seeFig. 28.3) is affected by various physiological states including stress and anxiety (which activate the axis) and sleep/wake cycles.
Corticotropin-releasing hormone (CRH), a 41amino acid peptide produced by the hypothalamus andsecreted into the hypothalamic-hypophyseal portal circulation, stimulates the anterior pituitary corticotrophs torelease as well as synthesize adrenocorticotrophic hormone(ACTH).
ACTH stimulates the conversion of cholesterolto pregnenolone in the adrenal cortex. This stimulationresults in:■■■Increased cortisol synthesis by the zona fasciculata.Higher androgen production by the zona reticularis(although androgen production is also probably affectedby other factors as well).Permissive effects on aldosterone production by the zonaglomerulosa.
ACTH is necessary but not by itself sufficient stimulus for aldosterone synthesis, which is underprimary control by other factors.The 39 amino acid polypeptide hormone ACTH is firstsynthesized as a 241 amino acid prohormone called proopiomelanocortin (POMC). Although ACTH is the main physiologically relevant product of POMC in corticotrophs of theanterior pituitary, POMC is produced in various other sites,including the hypothalamus and brainstem.
The multiple products of POMC include ACTH, β-lipotropin, α-melanocytestimulating hormone (α-MSH), β-MSH, and the endogenousopioid β-endorphin, among others. The relevance of endogenous production of some of the products in humans is limitedor not well-defined in some cases.
For example, α-MSH is produced by the pituitary’s pars intermedia (see Fig. 26.3) andpromotes pigmentation of skin. However, although the parsintermedia produces α-MSH in the fetus, there is little or nointermedia present in adults. Interestingly, because α-MSHconsists of the first 13 amino acids of ACTH, when ACTH isproduced in excess (for example, by an ACTH-secreting tumor),increased skin pigmentation can occur.330Endocrine PhysiologyInferior vena cavaInferior phrenic arteriesEsophagusLeft inferior phrenic veinRight superiorsuprarenal arteriesLeft superior suprarenal arteriesRightsuprarenal veinLeft suprarenal glandRightsuprarenal glandCeliac trunkRight middlesuprarenal arteryLeft middle suprarenal arteryRight inferiorsuprarenal arteryMedullaCortexPostganglionicCeliac fibers supplyganglion blood vesselsLeft inferiorsuprarenal arteryLeft suprarenal veinLeft renal artery and veinAbdominal aortaRight renal artery and veinSuperior mesenteric arteryInferior vena cavaPreganglionicfibers ramifyaround cellsof medullaSuprarenal glandFigure 28.1 Adrenal Gland Structure The two adrenal glands are located above the kidneys andbelow the diaphragm in the retroperitoneal space.
The outer cortex of the adrenal gland produces steroidhormones, whereas the inner medulla synthesizes and releases catecholamines.The predominant adrenal effect of activation of the HPA axisis release of cortisol. ACTH is secreted in a pulsatile mannerin response to variations in CRH release, with peak secretionearly in the morning, in the hours before awakening, andlowest secretion just before sleep. Stress (e.g., hypoglycemia,heavy exercise, severe pain, surgery, trauma, and infection) isa major stimulus for activation of the HPA axis and thereforecortisol release.Negative feedback regulation in the HPA axis involves longloop feedback by cortisol on the pituitary gland and hypothalamus and short-loop feedback of ACTH on hypothalamicCRH release (see Fig.
28.3).ACTIONS OF CORTISOLCortisol, secreted in response to HPA activation, has a widearray of physiological effects (Fig. 28.4). Like other steroidhormones, it binds to specific cytoplasmic receptors in targetcells. The receptor-hormone complex is translocated to thenucleus, where it affects the transcription of specific genes.The term glucocorticoid stems from the fact that cortisolraises blood glucose levels; some of the other products of thesteroid synthesis pathways, notably corticosterone, also haveglucocorticoid activity. Notably, many of the effects of cortisolare permissive, meaning that the hormone does not directlycause a particular effect but is necessary for that effect to occurAdrenal Hormones331CapsuleZona glomerulosaClear cells (ⴛ700,H&E stain)Zona fasciculataCompact cells(ⴛ700, H&E stain)Zona reticularisMedullaANormal humansuprarenal glandMedulla (ⴛ700,chromaffin stain)Suprarenal artery (one of many)Human suprarenalgland after administration of crude ACTHCapsular plexusCapsuleGlomerulosaCortical capillariesFasciculataMedullary arterioleReticularisMedullary capillariesMedullaBCentral veinMuscle veinsSchematic stereogram of intrinsicsuprarenal circulationFigure 28.2 Adrenal Gland Histology The highly vascularized adrenal (suprarenal) glands comprisean outer cortex and inner medulla.
The cortex synthesizes the steroid hormones aldosterone, cortisol, andandrogens, respectively, in its zona glomerulosa, zona fasciculata, and zona reticularis. ACTH administrationresults in increased cell size and steroid biosynthetic activity mainly in the zona fasciculata but also in thezona reticularis (A).
The medullary chromaffin cells synthesize and release catecholamines (mainly epinephrine) into the bloodstream in response to sympathetic nervous system activation. The blood supply to theadrenal gland is provided by the suprarenal arteries (B). ACTH, adrenocorticotropic hormone.in response to another stimulus. For example, cortisol stimulates the synthesis of enzymes involved in gluconeogenesis(synthesis of glucose from specific gluconeogenic amino acidsor from lactate, pyruvate, or glycerol). In general, the effectsof glucocorticoids can be categorized as metabolic, antiinflammatory, and immunosuppressive (see Fig. 28.4).Metabolic Effects of GlucocorticoidsThe major metabolic effects of cortisol at normal levels are:■■■■Stimulation of gluconeogenesis.
As noted, this is a permissive action of cortisol, which induces synthesis ofenzymes involved in hepatic gluconeogenesis.Protein catabolism to provide substrate (amino acids)for gluconeogenesis.Lipolysis in adipose tissue.Inhibition of insulin-stimulated glucose uptake bymuscle and adipose tissue. Because of this action, as wellas stimulation of gluconeogenesis, cortisol is considereda diabetogenic hormone.332Endocrine PhysiologySleep/wake cycleAnxietyStress (e.g., infection, trauma, surgery)HypothalamusCRHCRHPituitaryACTHCH2OHACTHCholesterolCortisolCYP11A1HOC OOH⌬5-Pregnenolone3-HSD 2OCYP17Progesterone17␣-OH-PregnenoloneCYP21A23-HSD 2CYP17*11-Deoxycorticosterone17␣-OH-ProgesteroneCYP21A2CYP11B1CorticosteroneCYP11B2Dehydroepiandrosterone(DHEA)11-DeoxycortisolCYP11B1sulfotransferaseCYP17*CORTISOLALDOSTERONECH2OHOC OHCHOOHSO3ODHEA-SULFATE(DHEA-S)OANDROSTENEDIONETESTOSTERONEOOESTRADIOLOHOOHHOGonadsFigure 28.3 Adrenal Cortical Hormones Adrenal mineralocorticoid (aldosterone), glucocorticoid(cortisol), and androgens (dehydroepiandrosterone and androstenedione) are synthesized from cholesterolthrough the biosynthetic pathways illustrated.
ACTH stimulates the conversion of cholesterol to Δ5-pregnenolone by the enzyme CYP11A1; the conversion of Δ5-pregnenolone to various products is dependenton additional enzymes in the various zones of the adrenal cortex. The adrenal gland also synthesizessmall amounts of other steroids (e.g., testosterone and estradiol). Negative feedback on ACTH and thehypothalamic-releasing hormone CRH is accomplished by cortisol.
ACTH, adrenocorticotropic hormone;CRH, corticotropin-releasing hormone.As a result of these various effects, normal levels of glucocorticoids stimulate gluconeogenesis and, in the well-fed state,storage of glucose in the liver in the form of glycogen. Theseactions become extremely important in maintaining bloodglucose levels during periods of fasting.As is the case for many hormones, the consequences of excessglucocorticoids are in part, but not wholly, predictable basedon their normal actions. The metabolic effects of excess glucocorticoids include:■■Muscle wasting and thinning of skin, due to proteincatabolism and inhibition of protein synthesis.
In excess,cortisol is a catabolic hormone.Bone resorption, due to imbalance between osteoclasticand osteoblastic activity.Adrenal HormonesCirculationMuscleLiverAmino acidscatabolic(antianabolic)actionMusclewasting333Glycogen(gluconeogenesis)Cortisol inhibitsinsulin-stimulatedFatuptake of glucosedeposition by muscle and(centripetal) fat cellsIncreasedglucoseoutputResorptionof bonematrixPancreasCalciumresorptionCa2+Increasedinsulinoutput Increased renalexcretionof calciumH2OInitiallyincreasedantibodyreleaseLymphnodelysisDecreasedconnective tissueIncreasedglomerularfiltration(water diuresis)K+, H+Na+EventuallydecreasedantibodyproductionPotassium losssodium retentionNorepinephrineMaintenanceof arterialtone andblood pressurewithnorepinephrineDecreased fibroblastproliferationIncreasedneuralexcitabilityInterleukin productionNeutrophil recruitmentLymphocytesNeutrophil phagocytosisNeutrophilsAntiallergic actionAnti-inflammatory actionFigure 28.4 Actions of Cortisol Cortisol has a wide array of actions, including muscle wasting, gluconeogenesis, hyperglycemia, anti-inflammatory and anti-immune effects, and insulin resistance.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
