BASIC ENDOCRINE MECHANISMS 2010 CMB for RL.docx by linzhengnd


									                            BASIC ENDOCRINE MECHANISMS
                                      Joel Michael, PhD
                      Department of Molecular Biophysics and Physiology
                                         1273 Jelke

Resource material:

Levy, Koeppen, Stanton, Principle of Physiology, 4th edition, Chapter 41

Learning Objectives:

The student should be able to:

1.    define hormone, receptor, target cell.
2.    distinguish endocrine, paracrine, neuroendocrine and synaptic chemical
      messenger systems.
3.    list the three chemical classes of hormones.
6.    describe the processes that determine the concentration of a circulating
7.    describe the feedback regulation of hormone secretion using specific
8.    predict the results of disturbances to an endocrine feedback system
      occurring any where in the system.
9.    describe the importance of pulsatile and diurnal secretion of hormones.
10.   describe the steps in the actions of steroid hormones mediated by binding to
      mobile receptors.
11.   describe the steps in the actions of peptide hormones mediated by binding
      to fixed receptors
12.   define and give examples of direct and permissive actions of hormones.
13.   define the trophic effect of a hormone.
14.   define antagonistic and synergistic effects of two hormones.
15.   describe common causes of hypo- and hypersecretion of hormones and
      predict the consequences of each for any hormone.
16.   describe the anatomical relationship between the hypothalamus and the
      pituitary, and the functional significance of this relationship.
17.   describe the structure and the significance of the hypothalamico-
      hypophyseal portal system.
18.   list the hormones released by the posterior pituitary, the mechanisms
      controlling their release, and their peripheral functions.
19.   describe the feedback control of hormone secretion at all three levels of the
      hypothalamic-pituitary-target organ axis.

Key Words

“extranuclear”           negative feedback systems
amines hormones          permissive effect
antagonistically         posterior pituitary
anterior pituitary       protein hormones
cell membrane            pulsatile
chemical messengers      receptors
diurnal                  second messengers
dose-response            short loop feed back
ductless                 steroids hormones
endocrine glands         synergistically
enzymes                  target cell
fixed receptors          target cells
half-life                the hypothalamic-pituitary-target organ
hormones                    axis
hypothalamus             transport proteins
information              trophic
intranuclear receptors   trophic effects
long loop feedback       up and down-regulation
mobile receptors

I.     Endocrine Systems: An Overview                                             (FIG. 1)

       A.    Endocrine glands are identifiable groups of cells that manufacture and
             secrete specific chemical messengers called hormones.

       B.    Hormones are chemical messengers that circulate in the blood and alter
             the function of all those cells (target cells) possessing receptors for that

       C.    Target cells possess receptors which bind the hormone, resulting in
             altered behavior of the cell (the response).

II.    Endocrine Glands:

       A.    are capable of synthesizing and releasing hormones in response to
             appropriate signals.

       B.    are ductless, and the hormones they release either diffuse to neighboring
             target cells or diffuse into capillaries and are carried throughout the body
             by the circulation.

       C.    may require the presence of a trophic substance to maintain their integrity
             and function.

       D.    A list of the endocrine glands we will be considering and their hormones
             can be found in Figure 1-2                                          (FIG. 2)

III.   Basic Properties of Hormones

       A.    Hormones control or determine the activity of target cells at a distance.
             They are one example of cell-cell communications.

       B.    Hormones carry information that cause target cells to alter their function

             1. Hormones are not themselves enzymes, although they ultimately alter
                enzyme levels and/or activity in their target cells.
                                                                           (FIG. 1)

                                      FIGURE 1

Endocrine systems and the ways in which they exert their effects on target cells.
NOTE: (1) hormone must bind to receptor to produce any effect and (2) the
physiological effect arises from changes in intracellular enzyme activity.
(3) Every cell has receptors for many different hormones each of which
simultaneously contributes to determining cell function.
                                                                  Source: JAM.

ENDOCRINE                                 HORMONE                                 EFFECTS

Hypothalamus          Thyrotropin releasing hormone (TRH)              Stim. TSH release
                      Corticotropin releasing hormone (CRH)            Stim. ACTH release
                      Gonadotropin releasing hormone (GnRH)            Stim. FSH & LH release
                      Growth hormone releasing hormone (GHRH)          Stim. GH release
                      Growth hormone inhibiting hormone (GHIH)         Inhibits GH release
                      Prolactin releasing hormone (PRH)                Stim. prolactin release

                      Prolactin inhibiting hormone (PIH)               Inhibits prolactin release
Anterior pituitary    Thyroid stimulating hornone (TSH)                Stim. T3/T4 synth./rel.

                      Adrenocorticotropic hormone (ACTH)               Stim. cortisol release
                      Growth hormone (GH)                              Stim. somatomedin release
                                                                       from liver; significant effects
                                                                       on metabolism

                      Follicle stimulating hormone (FSH)               Stim. follicle growth and
                                                                       estradiol synthesis

                      Luteinizing hormone (LH)                         Stim. ovulation and ovarian
                                                                       estradiol and progesterone
                      Prolactin                                        Stim. milk production

Posterior pituitary   Vasopressin (antidiuretic hormone-ADH)           Stim. renal reaborption of
                                                                       H20; vasoconstricts

                      Oxytocin                                         Stim. milk secretion and
                                                                       uterine contraction

Thyroid gland         Tetraiodothyronine (thyroxin = T4)               Precursor form of T3
(follicular cells)
                      Triiodothyronine (T3)                            Stim. growth, different-iation,
Thyroid gland         Calcitonin (CT)                                  Decreases plasma [Ca ]
(C cells)

Adrenal cortex        Aldosterone                                      Stimulates Na retention by
                      Cortisol                                         Increased carbohydrate
                                                                       metabolism (blood glucose
                      Androgens                                        Reproductive function
                                        FIGURE 2 (continued on next page)

ENDOCRINE GLAND                     HORMONE                             EFFECTS

Adrenal medulla       Epinephrine/Norepinephrine         Many stimulatory/inhibitory effects on
                                                         nerves, glands, smooth muscle
Pancreas (islets)     Insulin ($-cells)                  Decrease blood glucose concentration

                      Glucagon ("-cells)                 Increases blood glucose concentration

                      Somostatin (D-cells)               Decrease secretion of other islet
Parathyroid           Parathyroid hormone (PTH)          Increases blood [Ca ]

Ovaries               Estrogen                           Stimulate female sexual development
                                                         and functions

                      Progersterone                      Increase uterine and mammary gland

                      Inhibin                            Decreases FSH secretion
Testes                Testosterone                       Increases male sexual development and

                      Inhibin                            Decreases FSH secretion

Placenta              Estrogen                           Stimulation of uterine and breat growth

                      Chorionic gonadotropin             Increases progesterone synthesis by
                                                         corpus luteum
Skin                  Vitamin D                          Increases blood [Ca ]

Liver                 Somatomedin (=IGF-1)               Stimulates growth

                                           FIGURE 2 (continued)

         A list of the major endocrine glands, the hormones that are released by the
         endocrine cells, and the major physiological effects of these hormones (generally
         very much simplified). We will discuss these hormones in different blocks
         throughout the year. DO NOT MEMORIZE!                               Source: JAM

IV.    Chemical Nature of Hormones                                              (FIG. 3)

       A.   Protein hormones are made of 50 or more amino acids, while peptide
            hormones have fewer than 50 amino acids.

            1.    Synthesis of preprohormone occurs in ribosomes on the rough
                  endoplasmic reticulum.

            2.    Prohormone cleaved off in the Golgi apparatus.

            3.    Hormone packaged in secretory vesicles for storage.

            4.    Hormone release occurs from vesicles.

       B.   Steroids hormones are ALL synthesized from cholesterol

            1.    Cells take up low-density lipoprotein (LDL) and make cholesterol

            2.    There is a complex pathway by which the steroid hormones can be

            3.    Steroid hormones are not stored, but are released as they are

            4.    The similarity of the chemical structures of cortisol and aldosterone

      C.    Amines hormones are derived from tyrosine

            1.    They are synthesized either in specialized extracellular
                  compartment (thyroid hormone) or via enzymes in the cytosol
                  (adrenomedullary catecholamines).

            2.    They are stored and secreted on demand.

CHEMICAL                        HORMONE              # OF AAs   MAJOR SOURCE

Peptides & Proteins   ADH (vasopressin)                   9     Posterior pituitary
                      GnRH                                10    Hypothalamus
                      TRH                                 3     Hypothalamus
                      Somatostatin                        14    Hypothalamus &
                      Insulin                             55    Pancreas (-cells)
                      Glucagon                            29    Pancreas (-cells)
                      Growth hormone                      191 Anterior pituitary
                      Prolactin                           198 Anterior pituitary
                      PTH                                 84    Parathyroid
                      Calcitonin                          32    Thyroid (C cells)
                      ACTH                                39    Anterior pituitary
                      Somatomedin (IGF-1)                 70    Liver, bone
                      Inhibin                                   Ovaries
Glycoproteins         FSH                                       Anterior pituitary
                      LH                                        Anterior pituitary
                      Chorionic gomadotropin                    Placenta
                      TSH                                       Anterior pituitary
Steroids              Estrogen                                  Ovaries, placenta
                      Progesterone                              Corpus luteum, placenta
                      Testosterone                              Testes
                      Glucocorticoids                           Adrenal cortex
                      Aldosterone                               Adrenal cortex
                      Vitamin D metabolites                     Liver, kidneys
Amines                Dopamine                                  CNS
                      Epinephrine/norEpi                        Adrenal medulla
                      Thyroid homrones                          Thyroid

                                              FIGURE 3

       Chemical classification of hormones. Peptides have fewer than 50 amino acids,
       while protein hormones have 50 or more.    DON’T MEMORIZE!
                                                                         Source: JAM.

V. Transport of hormones in the blood

      A.     Protein and peptide hormones, and the amine hormones dopamine and
             epinephrine, are water soluble and hence are carried in plasma as simple

      C.     Steroid hormones and thyroid hormone have a very low solubility in water
             and are carried in the blood bound to specific plasma protein transporters.
                                                                                 (FIG. 4)

             1.     These transport proteins are made in the liver and their production
                    is determined by and can be altered by metabolic and endocrine

             2.     Some transport proteins only bind a specific hormone, while others
                    are nonspecific.

             3.     Only the small percentage of the transported hormones is present
                    unbound and in solution in the plasma, but it is only the unbound
                    hormone that is free to diffuse to its target cells. Thus, only
                    the unbound hormone is biologically active.

             4.     Changes in the concentrations of these transport proteins can thus
                    affect hormone activity.

              Transport protein                   Hormone transported
       CBG (transcortin)                  Corticosteroids (cortisol)
       TGB (thyroxine-binding globulin)   T3/T4
       SHBG (sex hormone-binding          Testosterone, estrogen

       Albumin                            Steroid hormones (non-specific)
       Prealbumin (transthyretin)         T4 (and other biologically active substances)

       Many different plasma proteins     IGF-1 (somatomedin)

                                             FIGURE 4

      Plasma proteins involved in transporting non-soluble hormones (steroids and
      thyroid hormone) to their target cells. These proteins are manufactured in the
      liver. (Note that there are other transport proteins carrying other hormones; see
      Section 2).                                                            Source: JAM

VI.   Determinants of Free, Active Hormone Concentration                           (FIG. 5)

      A.    Rate of release from secretory cell is often determined by negative
            feedback systems

      B.    Binding to transport proteins (if any are involved); steroid hormones and
            thyroid hormone are transported bound to plasma proteins

      C.    Binding to target cell receptors

      D.    Degradation in liver and other peripheral tissues and excretion in urine or

            1.     Rate of removal from circulation referred to as the half-life
                                                                                   (FIG. 6)

                                                            FIGURE 5

                                                     The concentration of free
                                                     hormone in the plasma is
                                                     determined by the rate of
                                                     release (secretion), binding to
                                                     plasma proteins (if transport
                                                     proteins are involved),
                                                     metabolism (degradation) and
                                                     elimination (in urine or feces),
                                                     and binding to receptor proteins.
                                                     NOTE: hormones must bind
                                                     to a receptor to alter cell
                                                     function. Physiologically, the
                                                     concentration of free
                                                     hormone (and hence the
                                                     probability of binding to a
                                                     receptor) is altered by
                                                     changing the rate of secretion
                                                     (altering the stimuli that affect
                                                     the endocrine cell).
                                                                          Source: JAM.

                     Hormone                         Half-life*
                     Amines                          A few minutes
                     Thyroid hormones
                        T4                           As long as one week
                        T3                           A day or less
                     Polypeptides                    As long as 2/3 hour
                     Proteins                        As long as 3 hours
                     Steroids                        Up to 2 hours

                                           FIGURE 6

            The half-life (the time for half of the content of a hormone to be
            removed from the circulation) of the different classes of hormones.
            NOTE: the half-lives of hormones range from minutes to a week.

                                                                      Source: JAM.

                                TAKE HOME MESSAGE

The concentration of free hormone determines the probability of binding to a
cellular receptor. The principal physiological determinant of hormone
concentration is the rate of release of the hormone from the endocrine cell in
which it is made.

VII.   Control of Hormone Release From Endocrine Cells Is Determined By Different

       A.    Some physiological stimulus acting on secretory cell (for example, [K],
             [glucose], [Ca] etc.)                                             (FIG. 7)

       B.      Some other hormone acting on the secretory cells                   (FIG. 8)

       C.    Neural inputs (action potentials generated) to secretory cells (which are
             neurons) trigger the release of hormone.                            (FIG. 9)

                                           FIGURE 7

       One example of an endocrine system (one that regulates blood glucose) where
       the stimulus for hormone (insulin) release is some physiological parameter (here
       the plasma concentration of glucose) acting on the secretory cell (the beta cells).
       NOTE: This is, of course, a classical negative feedback system (regulating
       blood glucose).                                                      Source: JAM.

                                       FIGURE 8

A model of an endocrine system in which a number of hormones, acting on
different secretory cells (in hypothalamus, pituitary and adrenal gland) determine
the rate of hormone secretion and hence the biological response. NOTE: This is
also a classical negative feedback system, although obviously a more
complex one than the system illustrated in Figure 1-12.
Source:                                                        Devlin, Figure 23.2.

                                TAKE HOME MESSAGE

The rate of secretion of a hormone is almost always determined by a
negative-feedback system of some kind.

                                        FIGURE 9

Neural inputs to secretory cells can cause release of hormones such as ADH and
epinephrine.                                                      Source: JAM

D.    In addition to the effects of other stimuli determining the rate of release of
      hormones, there are “clock-like” inputs to endocrine cells that produce
      temporal variations in the rate of release.

      1.     Pulses of gonadal hormones result from the pulsatile
             (approximately two/hour) release of hormones all along the
             controlling axis                                         (FIG. 10)

      2.     Diurnal rhythm (24-hour clock) of release is visible in changing
             levels of ACTH and cortisol                                (FIG. 11)

                                                               FIGURE 10

                                                        Pulsatile fluctuations
                                                        (2/hour approximately) of
                                                        peripheral vein plasma
                                                        LH concentration and
                                                        portal vein plasma LHRH
                                                        (aka GnRH)
                                                        concentration (in female
                                                        sheep, but a similar effect
                                                        is known to occur in
                                                        women). Each pulse of
                                                        LHRH is responsible for
                                                        producing a pulse of LH.
                                                        Source: Berne and Levy,

                                       FIGURE 11
Diurnal rhythm of cortisol secretion; plasma cortisol is at its highest level around
8 a.m. NOTE: It is therefore essential that any assessment (for example, for
purposes of diagnosis) of cortisol levels (or any other hormones exhibiting
a diurnal rhythm) be done at the same time of day. Cortisol is normally
measured at 8 a.m.                               Source: Berne and Levy, 1993

VIII.   Mechanism of Action at Target Cell

        A.    For a hormone to alter the function of a cell, there must be receptors for
              that hormone in or on the cell.

        B.    Fixed receptors are located on the cell membrane: protein/peptide,
              dopamine, and the catecholamines all bind to cell membrane receptors.
                                                                               (FIG. 12)

              1.     Hormones binding to membrane receptors activate a variety of
                     intracellular second messengers that ultimately alter cell function by
                     altering the activity of intracellular enzymes.

        C.    Mobile receptors are present within the cell: steroid hormones andthyroid
              hormones bind to intranuclear receptors (and some also bind to receptors
              in the cytosol).

              1.     The “classical” model asserted that steroid hormones act only by
                     entering the nucleus and altering gene expression to alter the
                     production of enzymes (proteins).                           (FIG. 13)

              2.     However, there is now clear that at least some steroid hormones
                     also have “extranuclear” effects that result from their altering
                     cytosolic second messenger systems which can alter existing
                     enzyme activity (which produces rapid changes in cell function).
                     The consequences of hormone binding to extranuclear receptors
                     can also affect gene expression.                            (FIG. 14)

        D.    Every target cell (and that means every cell in the body) has receptors
              (membrane and intracellular) for a great many different hormones some
              of which act on the same cellular functions. The interactions between the
              hormones can be very complex.                                     (FIG. 15)

                                   TAKE HOME MESSAGE

   Hormones bind to either fixed, membrane bound receptors or to mobile,
   intracellular receptors. Binding of the hormone to its receptor triggers a
   cascade of events that ultimately lead to alterations in cellular enzyme
   activity. Cells have receptors for many different hormones.

                                      FIGURE 12

Binding of signaling hormones (protein, peptides, epinephrine/norepinephrine.) to
membrane receptors can activate a wide variety of intracellular signaling
mechanisms all of which ultimately alter enzyme activity. This results in the
biological response of the target cell.
                                       Source: Levy, Koeppen, Stanton, Figure 5-1

                                      FIGURE 13

The “classical” model of the mechanism of action of lipid soluble hormones
steroids, vitamin D, thyroid hormone). The hormone molecules enter the
cytoplasm where some bind to cytoplasmic receptors. The receptor-hormone
complex diffuses into the nucleus. Some hormone molecules diffuse directly
into the nucleus where they bind to receptors. In the nucleus, transcription and
translation are altered, resulting in a change in the production of enzymes
(proteins) and the generation of a biological response.
                                                       Source: Devlin, Figure 23.48

                                       FIGURE 14

  A model for the dual mechanism by which a steroid hormone like estrogen and,
it is believed, other steroid hormones produce their effects. (1) The “classical”
nuclear effect Involves estrogen diffusing into the cell and then into the nucleus
where it binds to a receptor. The result is alter gene expression
(transcription/translation) and altered enzyme activity in the cell. Cell function is
then changed. (2) There is also a non-nuclear (“non-genomic”) action that
involves estrogen binding to a cytosolic receptor and thus activating a cascade of
second messengers to alter enzyme activity. (3) Note that it is likely that some
of those second messengers are thought to also alter gene expression in the
                                                                     Drawing by JAM
          B. J. Cheskis, Regulation of cell signalling cascades by steroid hormones.
        Journal of Cellular Biochemistry, 93, 20-27, 2004.

                                   FIGURE 15

Cells have receptors for many chemical messengers and hormones. When the
receptor binds its ligand complex metabolic pathways are activated altering cell
function in a myriad of ways, often using the same reaction pathways. Multiple
the situation illustrated here and you can image the complexity involved in
understanding how endocrine mechanisms affect any particular function (for
example, regulation of blood glucose).                 Source: Devlin, Fig. 13.34.

IX.   Actions of Hormones on Target Cells

      A.      Dose-response relationship defines the relationship between the
              concentration of a hormone and the magnitude of the response (however
              measured) that results.                                        (FIG. 16)

           1. The maximum response can be measured, and expressed as some
              number of units of measure, or it can be expressed as a percentage of some
              defined maximal response.

              2.     Sensitivity is defined as the hormone concentration that is required
                     to produce 1/2 the maximum response

              3.     Maximum responsiveness can be decreased from normal levels by
                     such perturbations as decrease in the total number of functional
                     target cells, decrease in the number of receptors on each cell,
                     intracellular changes in enzymes etc.

              4.     Sensitivity can be decreased by a decrease in the number or
                     affinity of the receptors, increase in the rate of hormone breakdown

      B.      Up and down-regulation of receptor number (decreased hormone
              concentration leads to increased production of receptors by the target cell
              and visa versa).

      C.      Direct effects alters activity of target cells.                   (FIG. 17)

                                   FIGURE 16

The general shape of the dose-response curve. Alterations in this curve can
take the form of a change in maximal responsiveness (left lower panel) or a
change in sensitivity (right lower panel). Note the presence of a threshold
(hormone concentration must be greater than some value for any measurable
response to be visible)          Source: Levy, Koeppen, Stanton, Figure 41-9

                                      FIGURE 17

An example (do not worry about the details here, they will be discussed later) of
the direct alteration of target cell activity by a hormone. NOTE that insulin
stimulation of cells causes increased uptake of glucose, alteration of
enzymes affecting glucose metabolism, and increased entry of a variety of
electrolytes.                        Source: Levy, Koeppen, Stanton, Figure 43-7.

D.   Trophic effects maintain the metabolic activity of the target endocrine
     glands and stimulates release of hormone from these glands.

E.   Interactions between hormones can take a number of different forms:

          1.     Every cell has receptors for a MANY DIFFERENT HORMONES

          2.     In some cases two or more hormones “work together” to bring
                 about some biological response and in other cases two
                 hormones may “work against” each other in determining a
                 biological response

                  a. One form of interaction is for one hormone to have a
                     permissive effect on the action of a second hormone; a
                     threshold concentration of hormone X is required for
                     hormone Y to have any effect.

                 b.   Two hormones may interact synergistically. For example,
                      hormone X and Y “work together” to promote some
                      biological response, often non-linearly.  (FIGS. 18 & 19)

                 c.   Two hormones can interact antagonistically; hormone X
                      and hormone Y have opposite effects on a biological

          3.     All hormones act by altering the activities of enzymes and hence
                 altering the rate of metabolic pathways.

     4.        For any particular biological response, the magnitude of the
               response depends on the “summation” of the effects (some positive
               and some negative) of the many hormones that can affect the
               activities of the enzymes involved in creating that response.

                                  60                                     FIGURE 18
   Units of biological response   50                                 The concept of
                                                                     interaction between
                                                                     two hormones is
                                                                     illustrated. Note that
                                  20                                 in this case neither
                                                                     hormone alone has a
                                  10                                 major effect.
                                                                               Source: JAM.
                                       Resting   A   B         A+B

                                                         FIGURE 19

An actual example of the synergistic interaction of three hormones: cortisol (C),
epinephrine (E) and glucagons (G). Each of them alone increase blood glucose
levels, but G+E has a larger effect that either alone, and C+G+E has a very much
greater effect. From Eigler, N., Sacca, L., and Sherwin, R. S. (1979). Synergistic
increments of glucagons, epinephrine, and cortisol in dog. Journal of Clinical
Investigation, 23, 114.

X.    Endocrine pathophysiology                                                  (FIG. 20)

      A.   Hypo/hypersecretion (relative to "normal"): too little/too much will cause

      B.   Primary/secondary causes: since the secretion of almost every hormone
           is under negative feedback control, often by other hormones, the causes
           of hypo/hypersecretion can be at the endocrine tissue of interest (primary)
           or at any of the endocrine organs involved in feedback mechanisms

           1. Endocrine tumors typically hypersecrete the hormones made by
              the cells

           2. Damage of any sort to an endocrine gland will cause them to

XI.   Physiological functions of hormones                                       (FIG. 21)

      A.   Endocrine systems are involved with the regulation of a number of
           important physiological functions that include:

                1.     maintenance of the internal environment

                2.     regulation of metabolism (the availability of energy substrates)

                3.     growth and development

                4.     reproduction

           B.        You will be studying these endocrine functions in the blocks listed
                     in Figure 28.

                                 FIGURE 20

Causes of hypo- or hyper-secretion (and hence hypo- and hyper-function) in the
endocrine system. Altered endocrine function can be caused by dysfunction at
all of these different levels of organization.                  Source: JAM.

                            Hormones          Effectors controlled      Covered in:
Regulation of water
& electrolytes:
[Na+]                         aldosterone    Kidneys                  Urogenital block
[K+]                          aldosterone    Kidneys                  Urogenital block
osmolarity                    ADH            Kidneys                  Urogenital block
blood and ECF                 ADH            kidneys                  CV/Resp and
volume                        ANP                                     Urogenital
[Ca+2] & [PO4-2]       parathyroid h.        bone, kidneys            Musculoskeletal
                       calcitonin            bone                     block
                       vitamin D3            GI system
Control of             insulin               liver, muscle, adipose   GI/Metabolism
metabolism             glucagon              cells for all hormones   block
                       growth hormone
                       thyroid hormone
Growth and                    growth         All cells                Musculoskeletal
development                   hormone                                 block
Reproduction                  LH/FSH       male and female            Urogenital block
                              androgens    reproductive systems

                                        FIGURE 21
Endocrine systems play many roles in the regulation and control of physiologic
                                                                          Source: JAM.

XII.   Organization of the endocrine system: the hypothalamic-pituitary-target organ

       A.    The pituitary hangs down from the bottom of the hypothalamus
                     Bob: could expand the anatomy and/or embryo here (FIG. 22)

       B.    Two distinctly different endocrine systems are found here

             1.     Neurons making up the paraventricular and supraoptic nuclei in the
                    hypothalamus have axons that extend through the hypothalamus,
                    down the pituitary stalk, to the posterior pituitary (a neuro-
                    endocrine gland)

                    a. Axons end in close proximity to blood vessels making up the
                          hypophyseal circulation.
                    b.    Hormones entering the blood here travel throughout the

             2. Neurons in the hypothalamic-hypophysiotropic area of the
                hypothalamus have axons that extend into the vicinity of the
                hypophyseal portal circulation

                    a.     The hormones released here are carried by the hypophyseal
                           portal vessels down the stalk of the pituitary to the anterior
                    b.     In the anterior pituitary these hormones diffuse from the
                           blood to affect the behavior of anterior pituitary endocrine
                           cells. Hormones released from the anterior pituitary cells
                           enter the blood and are carried throughout the body.

       C.    Since the hypothalamus is part of the central nervous system, it integrates
             many neural inputs.

             1.     It serves as a pathway for "visceral" expression of CNS activity.

             2.     It co-ordinates

                    a.     the activity of the autonomic nervous system.
                    b.     the activity of the endocrine system.

             3. The hypothalamus also provides a means of producing endocrine
                 responses to stimuli detected by the central nervous system.

D.   The hypothalamus is a region of the brain where the blood-brain-barrier is
     weak and hence:

     1.    hormones can get into the cerebrospinal fluid to act on
           hypothalamic neurons, and

     2.    hormones released at the median eminence can move easily into
           the capillaries there.

                         TAKE HOME MESSAGE

The hypothalamus is the interface between the two "information
processing" systems 0f the body: the nervous system and the endocrine
system. Remember, the nervous system codes information by the
frequency of firing action potentials, and the endocrine system codes
information by the concentration of hormone that is present.

                                    FIGURE 22

A schematic overview of the anatomic and functional relationships between the
hypothalamus and the pituitary gland. Note that the posterior pituitary is an
extension of neural tissue that stores neurohormones produced in the
hypothalamus and it has its own arterial blood supply. In contrast the anterior
pituitary is endocrine tissue with a blood supply derived from veins that first drain
neural tissue in the median eminence (a portal circulation). NOTE: By this
arrangement the endocrine cells in the anterior pituitary are exposed to
high concentrations of neurohormones originating in the hypothalamus
and stored in the median eminence.
                                      Source: Levy, Koeppen, Stanton, Figure 45-1.

D. The release of HHH's is controlled by a variety of inputs:

      1.     neural inputs to the hypothalamus (or signals generated in the
             2.     hormonal feedback from the anterior pituitary (so-called
      short loop feed back; see below).
      3.     peripheral endocrine glands (so-called long loop feedback; see

E.    Some of the HHH's stimulate the release of hormones from their targets in
      the anterior pituitary and some inhibit the release of hormones from their

F.    Some anterior pituitary cells receive both releasing and inhibiting
      hormones from the hypothalamus.

G.    There are a number of feedback pathways linking the hypothalamus,
      anterior pituitary and target organs.                         (FIG. 23)

                                   FIGURE 23

Feedback pathways linking the hypothalamus, anterior pituitary and the target
endocrine organs. Remember, there is not always an ultra-short loop
                   Source: Redrawn from Levy, Koeppen, Stanton, Figure 45.5.

X111. Hormones of the Anterior Pituitary Bob: This might be the place to talk
      about the cells of the pituitary

      A.    The hormones secreted by the anterior pituitary cells fall into three

            1.     derivatives of ProOpioMelanoCortin (POMC)                     (FIG. 24)

                   a.     The secretory cells, corticotrophes, are basophilic.

            2.     glycoproteins: These peptide hormones are composed of two
                   chains.                                                (FIG. 25)

                   a.     The alpha chains of all these hormones are the same;
                          specificity and function is conferred by the beta chains which

                   b.     Thyrotrophes and gonadotrophes are basophilic.

                                                                     FIGURE 24

                                                             Cleavage of POMC to
                                                             yield ACTH and related
                                                                  Source: Devlin,
                                                             Figure 23.5.

                                         FIGURE 25

      Structural similarities among TSH, LH, HCG, and FSH are depicted
      schematically. TSH, LH, and FSH are released from the anterior pituitary while
      HCG is released from the placenta. Note that all share the same α-subunit.
                                                      Source: Berne and Levy, 1993.

     3. sommatomammotrophins: These are single chain polypeptides
     containing two or three S-S bridges.

           a.     Somatotrophes and mammotrophes are acidophils.

B.   All of the anterior pituitary hormones act via fixed receptors and have both
     trophic and stimulatory effects.


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