5Feedback regulation of hypothalmus/pituitary A prominent feature of each of the hormonal sequences initiated by the hypothalamic releasing hormones is negative feedback exerted upon the hypothalamic-pituitary system by the hormones whose production are stimulated in the sequence.
11Regulation of Growth Hormone Secretion GH secretion controlled primarily by hypothalamic GHRH stimulation and somatostatin inhibitionNeurotransmitters involved in control of GH secretion– via regulation of GHRH and somatostatin
12Regulation of Growth Hormone Secretion Neurotransmitter systems that stimulate GHRH and/or inhibit somatostatinCatecholamines acting via a2-adrenergic receptorsDopamine acting via D1 or D2 receptorsExcitatory amino acids acting via both NMDA and non-NMDA receptors
13Regulation of Growth Hormone Secretion b-adrenergic receptors stimulate somatostatin release and inhibit GHb-adrenergic receptors inhibit hypothalamic release of GHRH
14Regulation of Growth Hormone Secretion Additional central mechanisms that control GH secretion include an ultra-short feedback loop exerted by both somatostatin and GHRH on their own secretion
15Growth hormone vs. metabolic state When protein and energy intake are adequate, it is appropriate to convert amino acids to protein and stimulate growth. hence GH and insulin promote anabolic reactions during protein intakeDuring carbohydrate intake, GH antagonizes insulin effects-- blocks glucose uptake to prevent hypoglycemia. (if there is too much insulin, all the glucose would be taken up).When there is adequate glucose as during absorptive phase, and glucose uptake is required, then GH secretion is inhibited so it won't counter act insulin action.
16Growth hormone vs. metabolic state During fasting, GH antagonizes insulin action and helps mediate glucose sparing, ie stimulates gluconeogenesisIn general, during anabolic or absorptive phase, GH facilitates insulin action, to promote growth.during fasting or post-absorptive phase, GH opposes insulin action, to promote catabolism or glucose sparing
18Clinical assessment of GH Random serum samples not useful due to pulsatile pattern of releaseProvocative tests necessaryGH measurement after 90 min exerciseGH measurement immediately after onset of sleepDefinitive testsGH measurement after insulin-induced hypoglycemiaGlucose suppresses GH levels min after administration– patients with GH excess do not suppressMeasurement of IGF-1 to assess GH excess
19Acromegaly and Gigantism Caused by eosinophilic adenomas of somatotrophsExcess GH leads to development of gigantism if hypersecretion is present during early life– a rare conditionSymmetrical enlargement of body resulting in true giant with overgrowth of long bones, connective tissue and visceral organs.Excess GH leads to acromegaly if hypersecretion occurs after body growth has stopped.Elongation of long bones not possible so there is over growth of cancellous bones– protruding jaw, thickening of phalanges, and over growth of visceral organs
20Acromegaly Acromegaly A) before presentation; B) at admission Harvey Cushing’s first reported case
21GigantismIdentical twins, 22 years old, excess GH secretion
22ACTH: adrenocorticotropic hormone: synthesis and regulation of secretion Produced in corticotrophsACTH is produced in the anterior pituitary by proteolytic processing of Prepro-opiomelanocortin (POMC).Other neuropeptide products include b and g lipotropin, b-endorphin, and a-melanocyte-stimulating hormone (a-MSH).ACTH is a key regulator of the stress response
23ACTH synthesis Processing and cleavage of pro-opiomelanocortin (POMC)
24ACTH ACTH is made up of 39 amino acids Regulates adrenal cortex and synthesis of adrenocorticosteroidsa-MSH resides in first 13 AA of ACTHa-MSH stimulates melanocytes and can darken skinOverproduction of ACTH may accompany increased pigmentation due to a-MSH.
25Addison’s DiseaseDisease in which patients lack cortisol from zona fasiculata, and thus lacks negative feedback that suppresses ACTH productionResult: overproduction of ACTHSkin color will darkenJFK had Addison’s disease and was treated with cortisol injections
26b-endorphin Produced as a result of ACTH synthesis Binds to opiate receptorsResults in “runner’s high”Role in anterior pituitary not completely understoodOne of many endogenous opioids such as enkephalins
27Melanocyte-stimulating hormone (MSH) MSH peptides derived by proteolytic cleavage of POMCa-MSH has antipyretic and anti-inflammatory effectsAlso inhibits CRH and LHRH secretionFour MSH receptors identifiedMay inhibit feeding behaviorACTH has MSH-like activityHowever– MSH has NO ACTH like activity
29Regulation of ACTH secretion Stimulation of releaseCRH and ADHStressHypoglycemiaCRH and ADH both synthesized in hypothalamusADH (a.k.a. vasopressin) is released by posterior pituitary and reaches anterior pituitary via inferior hypophyseal artery.
30Regulation of ACTH secretion Deficiency of vasopressin (ADH) in hereditary diabetes insipidus is accompanied by decreased ACTH release.Vasopressin potentiates CRH at both hypothalamic and pituitary levels.Many vasopressinergic neurons also contain CRH resulting in co-release of two peptides into portal blood.
31ACTH Circadian pattern of release Highest levels of cortisol are in early AM following ACTH releaseDepends on sleep-wake cycle, jet-lag can result in alteration of patternOpposes the circadian pattern of growth hormone secretion
33ACTH Acts on adrenal cortex stimulates growth of cortex (trophic action)Stimulates steroid hormone synthesisLack of negative feedback from cortisol results in aberrantly high ACTH, elevated levels of other adrenal corticosteroids– adrenal androgensAdrenogenital syndrome: masculization of female fetus
34Glycoprotein hormones LH, FSH, TSH and hCGa and b subunitsEach subunit encoded by different genea subunit is identical for all hormonesb subunit are unique and provide biological specificity
35Glycoprotein hormones Glycoprotein hormones contain two subunits, a common a subunit and a distinct b subunit: TSH, LH, FSH and hCG.
36Gonadotrophs Cells in anterior pituitary that produce LH and FSH Synthesis and secretion stimulated by GnRH– major effect on LHFSH secretion controlled by inhibinPulsitile secretion of GnRH and inhibin cause distinct patterns of LH and FSH secretion
37LH/FSH Pulsatile pattern of secretion LH pulses are biphasic (every 1 minute, then large pulse at 1 hour)FSH pulses are uniphasicDiurnal– LH/FSH more pronounced during pubertyCyclic in females– ovarian cycle with LH surge at time of ovulationMales are not cyclic, but constant pulses of LH cause pulses of testosterone to be produced
39Regulation of LH/FSH Negative feed-back Inhibin produced by testes and ovaries Decreases FSH b-subunit expressionTestosterone from Leydig cells– synthesis stimulated by LH, feedsback to inhibit GnRH production from hypothalamus and down-regulates GnRH receptorsProgesterone– suppresses ovulation, basis for oral contraceptives. Works at both the level of pituitary and hypothalamus.
40Regulation of LH/FSHDopamine, endorphin, and prolactin inhibit GnRH release.Prolactin inhibition affords post-partum contraceptive effectOverproduction of prolactin via pituitary tumor can cause amenorrhea– shuts off GnRHTreated with bromocryptine (dopamine agonist)Surgical removal of pituitary tumor
41Regulation of LH/FSH Positive feedback Estradiol at high plasma concentrations in late follicular phase of ovarian cycle stimulates GnRH and LH surge– triggers ovulation
45Grave’s diseaseHyperthyroidism caused by circulating antibodies to the TSH receptor.Associated with diffuse goiter.Autoantibodies bind to TSH receptor and mimic the action of TSH itself leads to persistent stimulation of thyroid and elevated levels of thyroid hormones.
46Lacotrophs Site of production of prolactin Lactogenesis (milk synthesis) requires prolactinTonically inhibitedOf the anterior pituitary hormones, the only oneMultifactoral control, balance favors inhibitionDopamine inhibits prolactinProlactin releasing hormone is TRHOcytocin also stimulates prolactin releaseEstradiol enhances prolactin synthesis
47Prolactin Stimulates breast development and lactogenesis May be involved in development of Leydig cells in pre-pubertal malesImmunomodulatory effects– stimulates T cell functionsProlactin receptors in thymus
48Clinical assessment of PRL Single basal serum PRL measurement sufficient to determine excessPRL deficiency not a usual clinical concernPRL is only anterior pituitary with predominant negative control by hypothalamus– often elevated by lesions that interfere with portal blood flow.Elevated by primary PRL adenomas of pituitary
49Posterior pituitary hormones: ADH (AVP) and Oxytocin (hypothalamic hormones) Both are synthesized in the cell bodies of hypothalamic neuronsADH: supraoptic nucleusOxytocin: paraventricular nucleusBoth are synthesized as preprohormones and processed into nonapeptides (nine amino acids).They are released from the termini in response to an action potential which travels from the axon body in the hypothalamus
52Oxytocin: stimulates myoepithelial contractions In uterus during parturitionIn mammary gland during lactation
53Oxytocin: milk ejection from lactating mammary gland suckling is major stimulus for release.sensory receptors in nipple connect with nerve fibers to the spine, then impulses are relayed through brain to PVN where cholinergic synapses fire on oxytocin neurons and stimulate release.
54Oxytocin: uterine contractions Reflexes originating in the cervical, vaginal and uterus stimulate oxytocin synthesis and release via neural input to hypothalamusIncreases in plasma at time of ovulation, parturition, and coitusEstrogen increases synthesis and lowers threshold for release