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In addition to synthesizing vasopressin and oxytocin, the hypothalamus synthesizes and releases hypothalamic releasing andinhibitory hormones that are carried through the hypophy-General Principles of Endocrinology and Pituitary and Hypothalamic HormonesSteroid HormonesThyroid HormonesVitamin DPeptide andCatecholamineHormonesGrowthHormonesReceptorSignalgeneratorReceptorPPP␥␣PPPMonomericG proteinCell membrane␣CytoplasmHeterotrimericG proteinTyrosine kinaseactivitySecond messengers(cAMP, cGMP, Ca2+,IP3, diacylglycerol)NucleusTranscriptionfactorsNuclearreceptormRNADNARegulation of activity andconcentration of enzymesand other proteinsARegulation of metabolicpathways, cell growth, etc.AutocrineCelltype 1ParacrineEndocrineCelltype 1NeuroendocrineCelltype 1NeuronAxonHormoneHormoneHormoneHormoneBloodstreamCelltype 1BCelltype 2EffectBloodstreamCelltype 2Celltype 2EffectEffectFigure 26.2 Overview of Hormone Action Hormones act at target cells by binding to specific cellmembrane or cytosolic receptors, initiating a cascade of events that produces a physiological change (A).Binding to the receptor may result in generation of second messengers (e.g., cAMP, cGMP, IP3) or regulationof gene transcription.
True hormones (endocrine secretions) are released by “ductless glands” and arecarried by the bloodstream to their sites of action. They are part of a larger group of substances that includesautocrine, paracrine, and neuroendocrine secretions (B).Effect309310Endocrine PhysiologyInterventricularforamenThalamusHypothalamic sulcusParaventricularnucleusHypothalamic areaSupraopticnucleusHypothalamohypophyseal tractOptic chiasmMamillary bodyHypophysealstalkMedian eminencePars tuberalisInfundibular stemPars intermediaInfundibularprocessAdenohypophysisNeurohypophysisNeuralstalkParsdistalisCleftPosterior lobeConnectivetissue(trabecula)Anterior lobeFigure 26.3 Structure of Hypothalamus and Pituitary The anterior pituitary (adenohypophysis) and posterior pituitary (neurohypophysis)are derived from different embryonic tissues and function as separate glands.
Axons from hypothalamic nuclei extend to the posterior pituitary, wherehormones (oxytocin and vasopressin) are stored until released into the systemic bloodstream; other axons from hypothalamic nuclei extend to themedian eminence, where they release hormones into the hypophyseal portal circulation, which carries them directly to the anterior pituitary. At theanterior pituitary, these hormones inhibit or stimulate the release of various trophic hormones into the systemic blood.seal portal veins to the anterior pituitary and regulate thesecretion of trophic hormones (see Fig. 26.4).
This portal circulation allows direct transport of these hypothalamic hormones to the pituitary, without dilution in the generalcirculation. The major hormones secreted by the anteriorpituitary are as follows:■Thyroid-stimulating hormone (TSH), which stimulatesthyroid hormone synthesis and release by the thyroidgland.■■■■Adrenocorticotropic hormone (ACTH), which stimulates synthesis of adrenocortical steroids.Gonadotropins (LH and FSH), which promote steroidogenesis and gametogenesis by the testes andovaries.Prolactin, which stimulates milk production by thebreasts.Growth hormone (GH), which promotes the synthesisof insulin-like growth factors (IGFs) by the liver andother target tissues. IGFs produced by the liver areGeneral Principles of Endocrinology and Pituitary and Hypothalamic HormonesEmotional and exteroceptiveinfluences via afferent nerves311ParaventricularnucleusSupraopticnucleusHypothetical sitefor TSH stimulationHypothalamicarteryNeurosecretions from hypothalamus released into primary plexusof hypophyseal portal circulation after passing down nerve fibersSuperiorhypophysealarteryHypophyseal portal veins carry neurosecretions to adenohypophysisBlood levels—regulatory influenceNeurohypophysisSpecific secretory cells of adenohypophysis influencedby neurosecretions from hypothalamusGHTSHThyroidglandACTHIGFsFSHLHAdrenalcortexProlactinTestisMuscleOvaryBreast (milkproduction)ThyroidhormonesCortical Testosterone Estrogen ProgesteronehormonesFat tissueBone,muscle,organs(growth)Figure 26.4 Overview of Anterior Pituitary Function The anterior pituitary gland is controlled by releasing and inhibitory hormones secretedinto the hypophyseal portal circulation; these hormones reach the anterior pituitary directly through this portal circulation without entering the generalcirculation.
Under control of these factors, specific secretory cell types of the anterior pituitary secrete six major trophic hormones (TSH, ACTH, FSH,LH, prolactin, and GH), which act on distal endocrine glands. Trophic hormones and the target gland hormones have feedback effects on theseendocrine systems, designed to regulate blood levels of the target gland hormone. ACTH, adrenocorticotropic hormone; FSH, follicle-stimulatinghormone; GH, growth hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.released into the circulation, whereas IGFs produced inother tissues act locally, in an autocrine manner.
Growthhormone has growth-promoting and anabolic effects.Various anterior pituitary hormones are often referred to astrophic hormones, because they stimulate secretion of targetgland hormones (for example, gonadotropins stimulate steroidsynthesis and secretion by the gonads).FEEDBACK SYSTEMS AND RECEPTORREGULATION IN THE ENDOCRINE SYSTEMFeedback systems control blood hormone levels within normalranges, often with cyclic variations in levels. These feedbacksystems are an important aspect of homeostasis, providing forregulation of hormone levels and their physiological effects.The cyclic variations in secretion that occur for many312Endocrine Physiologyhormones are important in regulating complex processes suchas menstrual cycles and in the homeostatic responses todiurnal cycles in activity levels. Furthermore, many hypothalamic and pituitary hormones are released in a pulsatilemanner that allows for further fine-tuning of hormone releaseand action.Negative FeedbackBlood levels of endocrine secretions are controlled withinrelatively narrow ranges, with normal, often cyclic, variations.Typically, negative feedback systems control levels of hormones, whereby increased blood levels of a hormone inhibitits synthesis, maintaining the normal level (see Figs.
26.4 and26.5). For example, synthesis of the major male sex hormone,testosterone, is stimulated by the pituitary hormone luteinizing hormone (LH), which is released in response to a hypothalamic hormone, gonadotropin-releasing hormone (GnRH)(Fig. 26.5). The normal adult male level of testosterone ismaintained by negative feedback of testosterone on the production of LH and GnRH, as well as shorter feedback loops.In endocrine systems consisting of the hypothalamus, pituitary, and a target endocrine gland, feedback loops are classified as follows:■■■Long-loop feedback, in which hypothalamic and pituitary hormones in an endocrine axis are inhibited by thetarget gland hormone, as in the case of testosterone inhibition of GnRH and LH (as well as follicle-stimulatinghormone, FSH).Short-loop feedback, whereby an anterior pituitaryhormone inhibits the release of its associated hypothalamic hormone (e.g., inhibition of GnRH by LH).Ultrashort-loop feedback, in which secretion ofa hypothalamic hormone is inhibited by that samehormone.These multiple feedback systems allow for the fine-tuning ofhormone levels and participate in the generation of the cyclicvariations observed in levels of many hormones.Positive FeedbackAlthough negative feedback is the primary homeostaticmechanism in the endocrine system, there are rare examplesof positive feedback.
These positive feedback mechanismsare, by nature, self-limited, as dictated by the need for homeostasis in physiologic systems. The prime example of positivefeedback occurs during the menstrual cycle (see Fig. 26.5).In the late follicular phase of the cycle, estradiol levels riseabove a critical point, above which positive feedbackoccurs. The high estradiol concentration results in a surge inhypothalamic secretion of GnRH and pituitary secretionof LH and follicle-stimulating hormone (FSH), inducingovulation.
Ovulation and transformation of ovarian follicularcells into the corpus luteum signals the end of positivefeedback.Receptor RegulationThe cellular response to a hormone is dependent on the presence of specific receptors for the hormone. Although theresponse to a hormone is dependent on the concentration ofthe hormone, regulation in the endocrine system can alsooccur at the level of hormone receptors, by altering the numberof receptors or their binding affinity for a hormone.
In somecases, hormones induce down-regulation (reduction) of thenumber of their receptors or of the binding affinity of theirreceptors, as a type of negative feedback. For example, exposure of the ovary to increased levels of LH will result in reducedmembrane LH receptors. Hormones may also produce receptor up-regulation, in which the number or affinity of receptorsis increased. As an example, growth hormone increases thenumber of its receptors in some target tissues. When a hormoneaffects the number of its own receptors, the process is calledhomologous regulation.
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