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Endocrine Physiology lecture 3. Dale Buchanan Hales, PhD Department of Physiology & Biophysics. Anterior pituitary. Anterior pituitary : connected to the hypothalamus by hypothalmoanterior pituitary portal vessels. The anterior pituitary produces six peptide hormones:

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endocrine physiology lecture 3

Endocrine Physiologylecture 3

Dale Buchanan Hales, PhD

Department of Physiology & Biophysics

anterior pituitary
Anterior pituitary
  • Anterior pituitary: connected to the hypothalamus by hypothalmoanterior pituitary portal vessels.
  • The anterior pituitary produces six peptide hormones:
    • prolactin, growth hormone (GH),
    • thyroid stimulating hormone (TSH),
    • adrenocorticotropic hormone (ACTH),
    • follicle-stimulating hormone (FSH),
    • luteinizing hormone (LH).
feedback regulation of hypothalmus pituitary
Feedback 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.

regulation of growth hormone secretion
Regulation of Growth Hormone Secretion
  • GH secretion controlled primarily by hypothalamic GHRH stimulation and somatostatin inhibition
  • Neurotransmitters involved in control of GH secretion– via regulation of GHRH and somatostatin
regulation of growth hormone secretion1
Regulation of Growth Hormone Secretion
  • Neurotransmitter systems that stimulate GHRH and/or inhibit somatostatin
    • Catecholamines acting via a2-adrenergic receptors
    • Dopamine acting via D1 or D2 receptors
    • Excitatory amino acids acting via both NMDA and non-NMDA receptors
regulation of growth hormone secretion2
Regulation of Growth Hormone Secretion
  • b-adrenergic receptors stimulate somatostatin release and inhibit GH
  • b-adrenergic receptors inhibit hypothalamic release of GHRH
regulation of growth hormone secretion3
Regulation 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
growth hormone vs metabolic state
Growth 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 intake
  • During 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.
growth hormone vs metabolic state1
Growth hormone vs. metabolic state
  • During fasting, GH antagonizes insulin action and helps mediate glucose sparing, ie stimulates gluconeogenesis
  • In 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
clinical assessment of gh
Clinical assessment of GH
  • Random serum samples not useful due to pulsatile pattern of release
  • Provocative tests necessary
    • GH measurement after 90 min exercise
    • GH measurement immediately after onset of sleep
  • Definitive tests
    • GH measurement after insulin-induced hypoglycemia
    • Glucose suppresses GH levels 30-90 min after administration– patients with GH excess do not suppress
    • Measurement of IGF-1 to assess GH excess
acromegaly and gigantism
Acromegaly and Gigantism
  • Caused by eosinophilic adenomas of somatotrophs
  • Excess GH leads to development of gigantism if hypersecretion is present during early life– a rare condition
    • Symmetrical 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
acromegaly
Acromegaly

AcromegalyA) before presentation; B) at admission

Harvey Cushing’s first reported case

gigantism
Gigantism

Identical twins, 22 years old, excess GH secretion

acth adrenocorticotropic hormone synthesis and regulation of secretion
ACTH: adrenocorticotropic hormone: synthesis and regulation of secretion
  • Produced in corticotrophs
  • ACTH 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
acth synthesis
ACTH synthesis

ACTH

Processing and cleavage of pro-opiomelanocortin (POMC)

slide24
ACTH
  • ACTH is made up of 39 amino acids
    • Regulates adrenal cortex and synthesis of adrenocorticosteroids
    • a-MSH resides in first 13 AA of ACTH
    • a-MSH stimulates melanocytes and can darken skin
    • Overproduction of ACTH may accompany increased pigmentation due to a-MSH.
addison s disease
Addison’s Disease
  • Disease in which patients lack cortisol from zona fasiculata, and thus lacks negative feedback that suppresses ACTH production
  • Result: overproduction of ACTH
  • Skin color will darken
  • JFK had Addison’s disease and was treated with cortisol injections
b endorphin
b-endorphin
  • Produced as a result of ACTH synthesis
  • Binds to opiate receptors
  • Results in “runner’s high”
  • Role in anterior pituitary not completely understood
  • One of many endogenous opioids such as enkephalins
melanocyte stimulating hormone msh
Melanocyte-stimulating hormone(MSH)
  • MSH peptides derived by proteolytic cleavage of POMC
  • a-MSH has antipyretic and anti-inflammatory effects
    • Also inhibits CRH and LHRH secretion
  • Four MSH receptors identified
  • May inhibit feeding behavior
  • ACTH has MSH-like activity
  • However– MSH has NO ACTH like activity
regulation of acth secretion1
Regulation of ACTH secretion
  • Stimulation of release
    • CRH and ADH
    • Stress
    • Hypoglycemia
  • CRH and ADH both synthesized in hypothalamus
    • ADH (a.k.a. vasopressin) is released by posterior pituitary and reaches anterior pituitary via inferior hypophyseal artery.
regulation of acth secretion2
Regulation 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.
slide31
ACTH
  • Circadian pattern of release
    • Highest levels of cortisol are in early AM following ACTH release
    • Depends on sleep-wake cycle, jet-lag can result in alteration of pattern
  • Opposes the circadian pattern of growth hormone secretion
slide33
ACTH
  • Acts on adrenal cortex
    • stimulates growth of cortex (trophic action)
    • Stimulates steroid hormone synthesis
  • Lack of negative feedback from cortisol results in aberrantly high ACTH, elevated levels of other adrenal corticosteroids– adrenal androgens
  • Adrenogenital syndrome: masculization of female fetus
glycoprotein hormones
Glycoprotein hormones
  • LH, FSH, TSH and hCG
    • a and b subunits
    • Each subunit encoded by different gene
  • a subunit is identical for all hormones
  • b subunit are unique and provide biological specificity
glycoprotein hormones1
Glycoprotein hormones

Glycoprotein hormones contain two subunits, a common a subunit and a distinct b subunit: TSH, LH, FSH and hCG.

gonadotrophs
Gonadotrophs
  • Cells in anterior pituitary that produce LH and FSH
  • Synthesis and secretion stimulated by GnRH– major effect on LH
  • FSH secretion controlled by inhibin
  • Pulsitile secretion of GnRH and inhibin cause distinct patterns of LH and FSH secretion
lh fsh
LH/FSH
  • Pulsatile pattern of secretion
    • LH pulses are biphasic (every 1 minute, then large pulse at 1 hour)
    • FSH pulses are uniphasic
  • Diurnal– LH/FSH more pronounced during puberty
  • Cyclic in females– ovarian cycle with LH surge at time of ovulation
  • Males are not cyclic, but constant pulses of LH cause pulses of testosterone to be produced
regulation of lh fsh
Regulation of LH/FSH
  • Negative feed-back
    • Inhibin produced by testes and ovaries Decreases FSH b-subunit expression
    • Testosterone from Leydig cells– synthesis stimulated by LH, feedsback to inhibit GnRH production from hypothalamus and down-regulates GnRH receptors
    • Progesterone– suppresses ovulation, basis for oral contraceptives. Works at both the level of pituitary and hypothalamus.
regulation of lh fsh1
Regulation of LH/FSH
  • Dopamine, endorphin, and prolactin inhibit GnRH release.
    • Prolactin inhibition affords post-partum contraceptive effect
  • Overproduction of prolactin via pituitary tumor can cause amenorrhea– shuts off GnRH
    • Treated with bromocryptine (dopamine agonist)
    • Surgical removal of pituitary tumor
regulation of lh fsh2
Regulation of LH/FSH
  • Positive feedback
    • Estradiol at high plasma concentrations in late follicular phase of ovarian cycle stimulates GnRH and LH surge– triggers ovulation
thyrotrophs
Thyrotrophs
  • Site of TSH synthesis
  • Pattern of secretion is relatively steady
  • TSH secretion stimulated by TRH
  • Feedback control by T3 (thyroid hormone)
grave s disease
Grave’s disease
  • Hyperthyroidism 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.
lacotrophs
Lacotrophs
  • Site of production of prolactin
  • Lactogenesis (milk synthesis) requires prolactin
  • Tonically inhibited
    • Of the anterior pituitary hormones, the only one
    • Multifactoral control, balance favors inhibition
  • Dopamine inhibits prolactin
  • Prolactin releasing hormone is TRH
    • Ocytocin also stimulates prolactin release
    • Estradiol enhances prolactin synthesis
prolactin
Prolactin
  • Stimulates breast development and lactogenesis
  • May be involved in development of Leydig cells in pre-pubertal males
  • Immunomodulatory effects– stimulates T cell functions
    • Prolactin receptors in thymus
clinical assessment of prl
Clinical assessment of PRL
  • Single basal serum PRL measurement sufficient to determine excess
    • PRL deficiency not a usual clinical concern
  • PRL 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
posterior pituitary hormones adh avp and oxytocin hypothalamic hormones
Posterior pituitary hormones: ADH (AVP) and Oxytocin (hypothalamic hormones)
  • Both are synthesized in the cell bodies of hypothalamic neurons
  • ADH: supraoptic nucleus
  • Oxytocin: paraventricular nucleus
  • Both 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
oxytocin stimulates myoepithelial contractions
Oxytocin: stimulates myoepithelial contractions
  • In uterus during parturition
  • In mammary gland during lactation
oxytocin milk ejection from lactating mammary gland
Oxytocin: 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.
oxytocin uterine contractions
Oxytocin: uterine contractions
  • Reflexes originating in the cervical, vaginal and uterus stimulate oxytocin synthesis and release via neural input to hypothalamus
  • Increases in plasma at time of ovulation, parturition, and coitus
  • Estrogen increases synthesis and lowers threshold for release