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What is a hormone?

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Title: What is a hormone?


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Outline of todays lecture
  • Part I
  • Why YOU should care about hormones?
  • Definition--What is a hormone?
  • Introduction to behavioral endocrinology (4
    levels of analysis)
  • Common techniques in behavioral endocrinology
    (50 of today)
  • Part II
  • The endocrine system (other 50)
  • major hormones hypothalamic, pituitary, thyroid,
    GI, pancreatic, steroid, monoamines
  • Regulation
  • Revisiting question 1 and comparison with fMRI

3
Why should social-personality psychologists study
hormones?
  • Conservative estimate--the human brain is riddled
    with billions and billions of endocrine
    receptors?
  • Prima facie evidence of hormonal influence on
    behavior, thought, mood, emotion, personality?
  • Ignorance of the hormone-behavior link could have
    dire consequences
  • Corticotropin-releasing hormone (CRH) is a key
    neuroendocrine factor implementing endocrine,
    immune and behavioral responses to stress. The
    expression of CRH receptors was analyzed for the
    first time in pituitaries of suicide victims by
    in situ hybridization (2001--Molec. Psych). There
    was a shift in the ratio of the two major CRH
    receptors (R1 and R2) in the pituitaries of
    suicide victims, relative to those who died of
    natural causes. Causality unclear.
  • Todays lecture does NOT focus on the
    hormone-behavior link. That stuff you can pick
    up from journal articles, with new and exciting
    research coming out each week! Today we need to
    cover the bedrock, the core, the basics, the
    stuff that you need to function effectively and
    intelligently in this world.
  • And just to keep you from drifting off during the
    biological onslaught that is about to hit, lets
    take a peek at the final slide next.

4
What is a hormone?
Testosterone plays a crucial role in neuronal
function, but elevated concentrations may have
deleterious effects. Here it is shown that
supraphysiological levels of testosterone
(micromolar range) initiate the apoptotic
cascade. Short periods of elevated testosterone
levels (six to 12 hours), such as those resulting
from the use of muscle-building steroids,may lead
to "cell death" and may have long term effects on
brain function.
  • Hormones coordinate the physiology and behavior
    of an animal by regulating, integrating, and
    controlling its bodily functions.
  • Example The same hormone (e.g., Luteinzing
    Hormone--LH) that causes egg or sperm maturation
    also stimulates mating behavior in many species.
  • This dual function ensures that mating occurs
    ONLY when animals have mature gametes (eggs or
    sperm) available for fertilization.
  • Hormones are similar to neurotransmitters, but
    can operate over a greater distance and over a
    much greater temporal range than
    neurotransmitters.
  • Differences between hormones and
    neurotransmitters
  • Neural messages can only travel along existing
    nerve tracts hormonal messages can travel in the
    circulatory system thus any cell receiving blood
    is potentially able to receive a message.
  • Neural messages are digital, all-or-none events
    that have rapid onset and offset neural signals
    can take place in milliseconds plus, electrical
    signal can travel along myelinated axons at
    speeds up to 100 meters per sec! Hormonal
    messages are analog, graded events that can take
    seconds, minutes or hours to occur (more detail
    to follow).
  • How does a hormone exert its influence?
  • Only cells with receptors for that hormone can be
    influenced
  • Called target cells
  • Interaction of a hormone with its receptor leads
    to a genomic response whereby the hormone
    activates genes that regulate protein synthesis
    (e.g., up-regulation synthesis of a receptor for
    that hormone).
  • Some hormone effects are nongenomic.The
    monoamines.
  • Nongenomic (transcription-independent) effects
    are principally characterized by their
    insensitivity to inhibitors of transcription and
    protein synthesis. The most obvious experimental
    evidence suggesting their existence is rapid
    onset of action (within seconds to minutes).
    These rapid effects are likely not be mediated
    through intracellular receptors.

The dual effect of LH LH stimulates gonads to
produce gametes, and stimulates gonads to produce
testosterone
Action potentials propagate faster in axons of
larger diameter, other things being equal. They
typically travel from 10-100 m/s.
5
Hormonal Effects
Androgen receptor (computer image, left electron
micrograph, right)
  • Sufficient number of receptors must be available
    for hormonal effects to occur.
  • Popular belief that individual differences in
    behavior reflects differences in hormone
    concentrations. For example, it is assumed that
    roosters that crow frequently have more
    testosterone than roosters that seldom crow (or
    that aggressive men have higher T).
  • Not necessarily true!
  • Individual differences in behavior can reflect
    hormone concentrations,pattern of hormone
    release, numbers and location of hormone
    receptors, and the efficiency of those receptors
    in affecting gene transcription.
  • Hormones rarely change the function of a cell
    rather, they alter the rate of normal cellular
    function.
  • Thus, hormones affect cell morphology and size
    (including development of muscle and neuronal
    cells), and affect cell death (apoptosis)
    throughout the nervous system.
  • Although hormones obviously affect behavior, it
    is also true that behavior can influence hormonal
    levels and hormonal effects.

6
How might behavior affect hormones (most research
does not look at this)
little Dutch football fan
  • Behavior can and often does affect hormone levels
    which in turn can influence subsequent behavior.
  • World Cup Soccer Fans were assayed for
    testosterone before and after the Brazil-Italy
    final. Brazil won on penalty kicks. 11/12
    Brazil fans showed an increase in testosterone,
    whereas 9 of 9 Italian fans showed a decrease.
  • Testosterone concentrations were measured in four
    heterosexual couples over a total of 22 evenings.
    On 11 evenings, saliva samples were obtained
    before and after sex on the remaining 11
    evening, two samples were obtained, but there was
    no sex. Having sex caused an increase in
    testosterone in both men and women. No changes
    were seen in the no-sex nights. The early
    evening samples revealed no difference in
    testosterone concentrations between sex and
    no-sex evenings, suggesting that sex increases
    testosterone more than testosterone
    (concentrations) cause sex. Alternatively,
    physical exercise may have caused the increase
    (it increases CORT, which can correlate
    positively with T).

7
How does one go about answering a research
question in the field of behavioral
endocrinology? Example What causes the Zebra
Finch to sing?
  • (What causes Zebra Finches to Sing?)
  • Four correct answers, based on Levels of Analysis
  • Immediate causation mechanisms mediated by the
    nervous and endocrine systems
  • Example Singing in male zebra finches (In
    contrast to mammals in which structural
    differences in neural tissues have not been
    directly linked to behavior, structural
    differences in avian brains have been directly
    linked to a sexually dimorphic behavior bird
    song).
  • Female zebra finches never sing, even after
    testosterone treatment in adulthood.
  • Other species (wrens, canaries) show no or a
    diminished sex difference
  • The size of nuclei in two major brain circuits
    (HVc, RA, Area X) implicated in learning and
    production of bird song parallel sex differences
    in singing behavior (e.g., large dimorphisms in
    zebra finches,undetectable dimorphisms in wrens
    in which no singing difference is observed).
  • But why the sex difference in the zebra finch?
  • If female finches are treated with androgen soon
    after hatching, and then treated with androgen
    when adults, they dont sing, but they showed a
    small increase in the number of neurons in the
    song production region.
  • If female finches are treated with estrogen soon
    after hatching, then as adults, they show a
    marked increase in the number and size of neurons
    in this region, but still no singing.
  • However, if treating with estrogen soon after
    hatching and then treated with androgen as
    adults, they show the same size and number of
    neurons as their male conspecifics, and they
    SING. Conclusion Estrogens are necessary to
    organize the neural machinery underlying the song
    system, and androgens activate it. Bird testes
    produce circulating androgens which enter neurons
    containing aromatse, an enzyme which converts
    androgens to estrogen. These neurons are
    generally found in the hypothalamus, as well as
    in the structures constituting the neural circuit
    controlling bird song.
  • Development
  • Behavioral responses change through the lifespan
    as a result of gene X environment interaction.

The mating dance of columba chippendalia is
virtually unique in the animal kingdom
8
Levels of Analysis (Zebra Finch song)
  • Hormonal events affecting the fetal and neonate
    can have profound consequences later in life.
  • Most research has focused on how early events
    influence adult behavior however, the decay of
    behavioral patterns during aging is also a new
    and expanding area to those pursuing
    developmental questions.
  • Possibly, zebra finches sing because they have
    undergone puberty or because they learned songs
    from their fathers.
  • Evolution
  • This approach involves many generations of
    animals and addresses the ways that specific
    behaviors change during the course of natural
    selection.
  • Biologists study the evolutionary bases of
    behavior in order to learn why behavior varies
    between closely related species as well as to
    understand the specific behavioral changes that
    occur during the evolution of a new species.
  • Behaviors rarely leave interpretable traces in
    the fossil record, so this approach relies upon
    comparing existing species that vary in
    relatedness (e.g., old v. new world monkeys).
  • Someone at this level might say that zebra
    finches sing because they are finches, and that
    all finches sing because they have evolved from a
    common ancestral species that sang.
  • Adaptive Function
  • Synonymous with adaptive significance role that
    behavior plays in the adaptation of animals to
    their environment and with the selective forces
    that currently maintain behavior.
  • Could be argued that male zebra finches sing
    because it will increase the likelihood of
    reproduction by attracting females to their
    territories and dissuading competing males from
    entering.
  • So, if we want to study HOW, then focus on
    questions of immediate causation and development.
  • If WHY, then questions of evolution and function.

9
How might hormones affect behavior
  • The study of the hormone-behavior relationship is
    organized around the idea that animals are
    composed of three interacting components
  • Input systems (sensory)
  • Integrators (CNS)
  • Output systems (e.g., muscles)
  • Example Removing the testes of the male zebra
    finch stops it from singing. Reinplant the
    testes, or provide the primary testicular
    hormone, testosterone, and singing resumes.
    Obviously, testosterone is involved in singing,
    but how?
  • Input Examine the sensory system. Does
    testosterone alter the birds sensory
    capabilities, making the environmental cues that
    elicit singing more salient? If this were the
    case, females or intruders might be seen or heard
    more easily.
  • CNS Testosterone could change the Neural
    Architecture or speed of neural processing.
    Higher processes (e.g., motivation, attention)
    might be influenced.
  • Effectors Testosterone concentrations might
    affect the muscles of the syrinx (the avian vocal
    organ).
  • This 3-part framework can aid in the design of
    hypothesis and experiments to help understand how
    hormones affect behavior.

10
Classes of evidence for determining
hormone-behavior interactions
  • 1st A hormonally-dependent behavior should
    disappear when the hormonal source is removed or
    actions of the hormone are blocked. Example--ADT.
  • 2nd After the behavior stops, restoration of the
    missing source or its hormone should reinstate
    the absent behavior. Again, ADT.
  • 3rd Hormone concentrations and the behavior
    should covary in practice, the behavior should
    be observed when concentrations are relatively
    high and never or rarely observed when
    concentrations are low.
  • This 3rd class of evidence is difficult to obtain
    because many hormones have a long latency of
    action (why? up-regulation.) and/or a long offset
    latency (why? down-regulation) and are released
    in a pulsatile manner. For example, a pulse may
    be released into the blood and then no more
    released for an hour or more, so a single sample
    will not provide an accurate picture of the
    endocrine status of the animal.
  • Another problem is that biologically effective
    amounts of hormones are TINY and thus difficult
    to measure accurately. Effective concentrations
    are measured in micrograms, nanograms, or
    picograms (10 to the negative 6th, 9th, or 12th,
    respectively).
  • Unfortunately, the 1st two classes of evidence
    are thus considered more reliable, but research
    on humans is typically limited to the 3rd (with
    exceptions--ADT, for example).

11
Common techniques in behavioral endocrinology
  • Ablation replacement
  • Bioassays
  • Immunoassays
  • Immunocytochemistry (ICC)
  • Autoradiography
  • Blot tests
  • In situ hybridization
  • Pharmacological Techniques
  • Genetic Techniques (transgenics and knockouts)

12
Common techniques in behavioral endocrinology
  • Ablation and replacement
  • 1. A gland that is suspected to the the source of
    the hormone affecting behavior is surgically
    removed
  • 2. Effects on behavior are observed
  • 3. Hormone is replaced, by reinplantation,
    injection of an extract from the gland or
    injecting a purified hormone
  • 4. Determination is made whether the observed
    consequences of ablation are reversed by
    replacement therapy.
  • 5. Is the surgically removed gland the hormonal
    source?

13
Common techniques in behavioral endocrinology
  • Bioassays
  • Once the existence of a hormone has been
    established, the next step is to identify the
    chemical processes involved in its actions.
  • Typically, this involved a test of its effects on
    a living animal (which can serve as a reliable,
    quantifiable response system on which to test
    hormonal extracts and chemical fractions).
  • A bioassay need not be conducted on the same
    species from which the hormone was obtained.
  • Example THE RABBIT TEST (or Friedman test).
  • Developed by Maurice Friedman in 1929 (used until
    the late 1950s). Used to test for the presence
    of human chorionic gonadotropic (hCG--a hormone
    released from the implantation site of a
    blastocyst. hCG prevents menstruation). hCG
    found in womens urine.
  • BTW, hCG produced by the rudimentary placenta
    that forms immediately after blastocyst formation
    (hCG maintains corpus luteal function during
    pregnancy--thus, progesterone secretion--and
    inhibits ovulation).
  • Urine injected into a rabbit, and if hCG present,
    rabbits ovaries would form corpora lutea, or
    yellow bodies (temporary ovarian endocrine
    structures formed following ovulation within 48
    hours and produce progestins--horomones that
    support pregnancy).
  • It is a common misconception that the injected
    rabbit would die only if the woman was pregnant.
    This led to the phrase "the rabbit died" being
    used as a euphemism for a positive pregnancy
    test. In fact, all rabbits used for the test
    died, because they had to be surgically opened in
    order to examine the ovaries. While it was
    possible to do this without killing the rabbit,
    it was generally deemed not worth the trouble and
    expense.
  • The rabbit test was better than the earlier mouse
    test (developed in 1928) which required 6 or more
    mice and 96 hours to complete.
  • However, if the rabbit was stressed, spontaneous
    corpora lutea formation occurs (in the absence of
    hCG), so there was a significant false positive
    rate.
  • In the frog test for pregnancy, a womans urine
    is injected into a male frog or toad. In 2-4
    hours, the animal would begin to produce sperm if
    the womans urine contained hCG. However, there
    were seasonal variations in frogs--in the summer,
    they had a greater tendency to produce false
    negatives.

corpus luteum
14
Common techniques in behavioral endocrinology
  • Immunoassays
  • Bioassays require a great deal of time, labor,
    and the sacrifice of many animals for every
    assay.
  • The development of the radioimmunoassay (RIA)
    reduced these problems and increase the precision
    with which hormone concentrations could be
    measured.
  • Based on competitive binding of an antibody to
    its antigen. An antibody produced in response to
    any antigen (defn any molecule that stimulates
    an immune response) has a binding site THAT IS
    SPECIFIC FOR THAT ANTIGEN.
  • Antigen molecules can be labeled with
    radioactivity, and an antibody cannot
    discriminate between an antigen that has been
    radiolabeled (or hot) and one that is normal
    (or cold). A given amount of antibody
    possesses a given number of binding sites for its
    antigen.
  • STEPS INVOLVED IN RIA
  • 1. First, inject the hormone of interest (e.g.,
    T) into an animal to raise antibody (anti-T)
  • 2. Then, collect antibody from blood, and purify.
  • 3. Develop a standard curve
  • Set up 5 or 6 reaction tubes, each containing the
    same amount of antibody, the same amount of
    radiolabeled hormone, and different amounts of
    cold purified hormone of known concentrations
    (from low to high concentration) .
  • (The radiolabeled and cold hormone compete for
    binding sites on the antibody, so the more cold
    hormone present, the less hot hormone will bind
    to the antibody)
  • 4. The quantity of hot hormone that was bound can
    be determined by precipitating the antibody and
    measuring its radioactivity.
  • 5. The concentration of hormone in an UNKNOWN
    sample can then be determined by subjecting it to
    the same procedure (substituting unknown sample
    for cold hormone in STEP 3) and comparing the
    results with the standard curve
  • The enzymoimmunoassay (EIA) works on the
    principle of competitive binding of an antibody
    to its antigen. The major difference is that
    EIAs do not require radioactive tags. Rather,
    the antibody is tagged with a compound that
    changes optical density (color) in response to
    binding with the antigen.
  • Example The home pregnancy test.
  • However, most EIAs provided quantitative
    information, and thus a standard curve is
    generated, so that different amounts of the
    hormone in question provide a color gradient that
    is read on a spectromoter. A similar technique
    is called enzyme-linked immunosorbent assay
    (ELISA).

15
Anatomy of an ELISA test
  • Animation of an HIV ELISA test (both positive and
    negative test--notice that you can test for
    presence of antigen (e.g., a hormone assay) or
    its complement antibody (viral assay).
  • http//www.biology.arizona.edu/IMMUNOLOGY/activiti
    es/elisa/technique.html

16
Common techniques in behavioral endocrinology
  • Immunocytochemistry (ICC)
  • ICC techniques use antibodies to determine the
    location of a hormone in the body.
  • Antibody molecules linked to marker molecules
    (usually a fluorescent dye) are introduced into
    dissected tissue from an animal, where they bind
    with the hormone or neurotransmitter of interest.
  • Tissue is examined under a fluorescent
    microscope, and concentrated spots of
    fluorescence will appear, indicating where the
    protein hormone is located.
  • Commonly used marker is the enzyme horseradish
    peroxidase.

human sputum cells
17
Common techniques in behavioral endocrinology
  • Autoradiography
  • Typically used to determine hormonal uptake and
    indicate receptor location.
  • An animal can be injected with a radiolabeled
    hormone, or the study can be conducted in vitro.
  • Top picture Human NMDA receptor (NDMA is a
    receptor for the amino acid glutamate, which is
    the most abundant neurotransmitter in the
    mammalian nervous system).
  • Bottom indicates transport in a young tomato
    plant The distribution of elements (e.g.
    micronutrients, pollutants) are visualized by
    autoradiographic techniques.

18
Other techniques in behavioral endocrinology
  • Blot tests (uses a technique called gel
    electrophoresis to separate proteins based on
    their length and weight (in kDa)
  • Used to determine presence of a particular
    protein or nucleic acid in a specific tissue.
  • Southern blot used to assay DNA
  • Northern blot used to assay RNA
  • Western blot used to assay proteins
  • In Situ Hybridization
  • Previous techniques can determine only whether or
    not a particular substance is present in a
    specific tissue, but in situ hybridization can be
    used to determine if the substance is produced in
    a specific tissue.
  • Used at the cellular level to examine gene
    expression.
  • More specifically, used to identify cells that
    are producing mRNA for a specific protein (e.g.,
    a hormone or neurotransmitter).
  • Called hybridization because a radiolabeled cDNA
    probe (cDNA, or complementary DNA is synthesized
    from mature mRNA by the enzyme reverse
    transriptase) is introduced into the tissue. If
    the mRNA of interest is present, the cDNA will
    form a tight association (i.e., hybridize) with
    it.

These are chromosomes from the canola seed
showing the location of various retrotransposons,
which are genetic elements that can amplify
themselves within a genome.
19
Other techniques in behavioral endocrinology
  • Pharmacological Techniques
  • Use of synthetic agonists (mimics) and
    antagonists (blockers) to determine endocrine
    functioning.
  • Some agents act to stimulate or inhibit endocrine
    functioning by affecting the release of hormones
    they are called general agonists/antagonists.
  • Others act directly on receptors, enhancing or
    negating the effects of the focal hormone these
    are receptor agonists/antagonists.
  • Example CPA is a powerful anti-androgen used
    clinically to treat male sex offenders (about 20
    of patient dont show the expected behavioral
    response). CPA binds to androgen receptors but
    doesnt activate them, thereby blocking effects
    of androgen.

20
Other techniques in behavioral endocrinology
  • Common genetic manipulations in behavioral
    endocrinology are the insertion (transgenic) or
    removal (knockout) of the genetic instructions
    encoding a hormone or hormone receptor.
  • Briefly The genetic instructions for each
    individual are contained in the DNA, located in
    the nucleus of nearly every cell.
  • Each gene (composed of a specific order of four
    nucleotides adenine, thymine, cytosine, and
    guanine) is determined by the sequence of
    nucleotides along the rails of the double
    helix.
  • To inactivate (knockout) a gene, you scramble the
    order of the nucleotides that make up the gene.
    The identification of the genome has been most
    successful in the mouse thus mice are most
    commonly used in knockout studies.
  • Knocking out a gene is more difficult than it
    sounds
  • gene of interest must be identified, targeted,
    and marked precisely.
  • A mutated form of the gene is then created (e.g.,
    mutating the marker gene via genetic
    engineering).
  • Embryonic stem cells are harvested and cultured,
    and the mutated gene is introduced into the
    cultured cells by microinjection.
  • A small number of the altered genes are
    incorporated into the DNA of the stem cells via
    recombination.
  • The mutated embryonic stem cells are inserted
    into normal embryos (blastocycts), which are then
    implanted into surrogate mothers.
  • Thats it!!!!
  • All of the cells from the mutated stem cells will
    have the altered gene the descendents of the
    normal embryonic cells will have normal genes.
  • Thus, the offspring will have a mixture of
    cells--some containing the mutated gene and some
    containing the normal (wild-type) gene.
  • This animal is called a chimera
  • The chimeras are then bred (interbred or bred
    with wild-type animals) to produce wild-type
    (/), heterozygous (/-), and homozygous (-/-)
    animals with respect to that gene. Behavioral
    performance can then be compared.
  • n.b In Greek mythology, a Chimera is a monster,
    depicted as an animal with the head of a lion,
    the body of a she-goat, and the tail of a dragon

21
Chimeras
  • Chimeric animals
  • Pictured on the right is a baby geep, made by
    combining a goat and sheep embryo. Notice the
    chimerism evident in the skin - big patches of
    skin on front and rear legs are covered with
    wool, representing the sheep contribution of the
    animal, while a majority of the remainder of the
    body is covered with hair, being derived from
    goat cells.
  • There is also some potential that this technique
    can be applied to problems such as rescue of
    endangered species. It is possible, for example
    to construct a goat-sheep chimera such that a
    goat fetus is "encased" in a sheep placenta. This
    enables a sheep to carry a goat to term, which
    will not occur if you simply transfer goat
    embryos into sheep (the sheep will
    immunologically reject the goat placenta and
    fetus). It may be possible to extend this
    procedure to allow embryos from severely
    endangered species to be carried by recipient
    mothers from another species.

22
Fat mice--Using all of the techniques discussed
previously to understand obesity
  • Effects of Leptin
  • Recently leptin (derived from Greek leptos,
    meaning thin) discovered as a hormone released
    from fat cells.
  • It is known that a specific mutation in mice on
    the ob gene can cause extreme obesity (in mice
    homozygous for defective ob).
  • Thus, these naturally-occuring mutants can be
    considered natural knockouts for the ob gene.
  • ob/ob mice have a pair of defective ob genes,
    overeat, are obese, and are sterile.
  • The ob gene normally codes for leptin, which is
    released into the bloodstream and travels to
    specific receptors in the CNS and elsewhere to
    regulate feeding and energy balance.
  • Although it has been known for a long time that
    the ob/ob mutation affects body weight in mice,
    only recently has the ob gene been cloned,
    inserted into a bacterial system, and thus
    purified leptin made available to researchers.
  • Replacement studies could now be done in which
    leptin was provided to ob/ob mice to determine if
    leptin replacement would ameliorate obesity.
  • It did (see mouse on the right (25g--average
    mouse is 15g one on the left is w/out
    replacement at 35g).
  • Availability of purified leptin allowed for the
    development of antibodies used to develop assays
    to determine blood concentrations.
  • RIA determined that there was no connection
    between plasma leptin concentrations and
    obesity/diatetes IN HUMANS.
  • A leptin ELISA was developed for rats, which
    determined that fasting or exposure to low
    temperatures caused leptin to fall.
  • Immunocytochemistry determined that leptin was
    present in both white (energy utilization) and
    brown (generation of body heat) adipose tissue.
  • Autoradiography determined that tagged leptin was
    found in a brain area located in the front of the
    third ventricle.
  • This tissue was then used to clone a leptin
    receptor
  • In situ hybridization found that the mRNA for the
    leptin receptor was expressed in the
    hypothalamus.
  • Efforts to cure obesity involved
    transgenics--treating ob/ob mice with a
    recombinant virus expressing mouse leptin cDNA,
    resulting in leptin production. A dramatic
    reduction in food intake and body mass resulted.
  • This treatment also reverses the sterility found
    in ob/ob mice.
  • However, only two (out of thousands) of obese
    humans displayed a ob mutation. Sadly, the
    effects of leptin on humans have been
    disappointing, dashing the Nobel dreams of more
    than a handful of psychologists.

23
The Endocrine System
  • Where do hormones come from?
  • They are produced by glands, and are secreted
    into the bloodstream.
  • Where do hormones go?
  • They travel to target tissues containing
    hormone-specific receptors.
  • What do hormones do?
  • By interacting with their receptors, they
    initiate biochemical events that activate genes
    to induce certain biological responses (e.g.,
    protein synthesis). In some cases,
    hormone-receptor interactions result in
    nongenomic effects on cellular function (these
    are fast, and are just now being studied in their
    role in mediating behavior).

24
Types of chemical communication
  • Intracrine mediation
  • regulation of intracellular events
  • Autocrine mediation
  • autocrine substances feedback to influence the
    same cells that secreted them.
  • Paracrine mediation
  • paracrine cells secrete substances that affect
    adjacent cells (e.g., nerve cells).
  • Endocrine mediation
  • endocrine cells secrete chemicals into the
    bloodstream where they may travel to distant
    target cells.
  • Ectocrine mediation
  • Ectocrine substances, such as pheromones, are
    released into the environment to communicate with
    others.

25
General Features of the Endocrine System
  • Endocrine glands are ductless
  • Endocrine glands have a rich blood supply.
  • Product of endocrine glands (hormones) are
    secreted into the blood stream
  • Hormones can travel to virtually any cell in the
    body (cells in the lenses of the eye are an
    exception--no blood supply)
  • Hormone receptors are specific binding sites,
    embedded in the cell membrane (in the case of
    peptide hormones) or in the cytoplasm (in the
    case of steroid hormones) that interact with a
    hormone or class of hormones
  • Exocrine glands have ducts or tubes (e.g.,
    salivary, sweat, mammary). Some glands have both
    endo- and exo- structures (e.g., pancreas)

26
The Endocrine Glands
In touch with his feminine side
27
Four classes of hormones
  • Protein peptide hormones
  • Steroid hormones
  • Monoamines
  • Lipid-based hormones (prostaglandins)

28
Cellular and molecular mechanisms of hormone
action--Protein Hormones (the majority of
hormones)
  • Protein hormones require a second messenger
    (i.e., a molecular middleman--typically, an
    enzyme or another protein) to transduce
    (conversion of one type of signal into another)
    the hormonal signal
  • In really simple terms, the hormone binds to the
    receptor which is coupled to a protein called G.
    When this mess is formed, a messenger called cAMP
    is created. cAMP combines with an enzyme that
    activates another enzyme which acts on the target
    substance (e.g., in the case of glucagon, this
    final enzyme converts glycogen into glucose).
  • Receptors are coupled to special proteins (G)
    that mediate intracellular events (all G proteins
    have 3 different subunits). The G protein
    receptor family includes glucagon, oxytocin, and
    vasopressin receptors.
  • When the hormone-receptor complex binds to G, G
    in turn activates adenylate cyclase, which in
    turn stimulates that formation of cyclic
    adenosine monophosphate, or cAMP.
  • When formed in response to a hormone-receptor
    bind, cAMP is referred to as the 2nd messenger
    (the hormone is the 1st messenger)
  • Once formed, cAMP can combine with an enzyme
    called protein kinase A (PKA), an enzyme that in
    turn activates (phosphorylates) another enzyme
    called phosphorylase kinase in a variety of
    cells.
  • For example, phosphorylase kinase A breaks down
    glycogen into glucose to provide intracellular
    energy.

glycogen
29
Cellular and molecular mechanisms of hormone
action--Steroid Hormones
  • Steroid hormones are fat soluble and move easily
    through cell membranes (as a result, these
    hormones are never stored but leave the cells in
    which they are produced almost immediately--nomadi
    c).
  • The precursor to all vertebrate steroid hormones
    is cholesterol (made from acetate in the liver).
  • In the blood, steroid hormones must bind to
    water-soluble carrier proteins to increase their
    solubility and the ability of the blood to carry
    them to their target tissues.
  • Upon arrival, they dissociate from their carrier
    proteins and diffuse through the cell membrane
    into the cytoplasm of the target cell, where they
    bind to cytoplasmic receptors.
  • The steroid-receptor complex is transported into
    the cell nucleus, where it binds to DNA sequences
    called hormone response elements and then either
    stimulates or inhibits the transcription of
    specific mRNA.
  • The precise mechanism through which binding to
    the hormone response elements occurs is unknown.
  • The transcribed mRNA migrates to the cytoplasmic
    rough endoplasmic reticulum, where it is
    translated into specific proteins or enzymes that
    produce the physiological response (much more on
    this later).
  • Note changes in the types of proteins a cell
    makes (aka, the gene products) can be observed
    within 30 minutes of hormone stimulation.

cholesterol
30
The major vertebrate hormones
  • Protein peptide hormones
  • Make up the majority of hormones
  • Protein hormones that are only a few amino acids
    in length are called peptide hormones (larger
    ones called protein or polypeptide hormones)
  • Include insulin, the glucagons, the
    neurohormones of the hypothalamus (monoamines),
    the hormones of the anterior pituitary, inhibin,
    calcitonin, parathyroid hormone, the GI hormones,
    leptin, and the posterior pituitary hormones
  • These hormones are blood-soluble (they dont need
    a carrier protein to travel to their target
    cells, as do steroid hormones). However, they
    may bind with other blood plasma proteins
  • The metabolism of a hormone is reported in terms
    of its half-life, which is the amount of time
    required to remove half of the (radioactively
    tagged) hormone from the blood
  • Generally, larger protein hormones have longer
    half-lives (e.g., growth hormone with 200 amino
    acids has a half life of 20-30 mins, whereas
    thyroid releasing hormone has 3 amino acids and a
    half life of fewer than 5 minutes).

Insulin (not Europe)
Human growth hormone
Too much human growth hormone (tumor on the
anterior pituitary)
31
Hypothalamic hormones
  • The peptide hormones secreted by the hypothalamus
    are best thought of as a special class of
    neurotransmitters that act on a variety of cells
    in the anterior pituitary.
  • Five releasing hormones and one inhibiting
    hormone have been isolated.
  • TRH--thyrotropin-releasing hormone
  • GHRH--growth hormone-releasing hormone
  • GnRH--gonadotropin-releasing hormone
  • MSH--melanotropin-releasing hormone
  • CRH--corticotropin-releasing hormone
  • Somatostatin--growth hormone-inhibiting hormone
  • Peptide and protein hormones vary in amino acid
    sequence (and vary by species--e.g., GnRH
    possesses a different sequence in frogs than in
    horses horse GnRH will not affect a frogs
    reproductive function (although salmon calcitonin
    is used in humans to promote bone
    mineralization). Hormones differ in species
    specificity.

Notice inter-species discrepancies in the 2nd
position (glycine), 8th position
(methionine),10th, 11th, and many others moving
forward. Calcitonin is a thyroid hormone. It
lowers blood levels of calcium by inhibiting
calcium release from bone. Interestingly, it is
regulated by blood calcium levels, not by
pituitary hormones.
32
Anterior Pituitary hormones
  • All protein hormones, all, ranging in length from
    39 to 220 amino acids.
  • Anterior pituitary is composed of three types of
    cells
  • Acidophils (these cells stain readily with acidic
    stains)
  • Basophils (stain readily with basic stains)
  • Chromatophils (do not take up either acidic or
    basic stains)
  • Basophil-secreted
  • Lutenizing hormone (LH), follicule-stimulating
    hormone (FSH), and thyroid-stimulating hormone
    (TSH) are secreted by basophils.
  • LH and FSH and controlled by hypothalamic GnRH.
    TSH is controlled by hypothalamic TRH.
  • All consist of 200-220 amino acids and have
    molecular weights of 25-35K daltons.
  • Note LH and FSH are known as gonadotropins
    because in response to GnRH, they stimulate the
    production of steroids in the gonads.
  • Acidophil-secreted
  • Growth hormone (GH) and prolactin (PRL)
  • TRH stimulates PRL secretion hypothalamic
    dopamine inhibits. GHRH and Somatostatin control
    GH.
  • 190-220 amino acids in length.
  • GH shows fair amount of species specificity.
  • GH stimulates body growth INDIRECTLY (does not
    induce skeletal growth).
  • Stimulates production of growth-regulating
    substances--somatostedins--by the liver and
    kidneys. Somatostedins cause bone to take up
    sulfates leading to growth.
  • GH also stimulates protein synthesis, fat
    mobilization,and hyperglycemia (because of its
    anti-insulin properties).
  • Prolactin (PRL) best known for promoting
    lactation in female mammals, but in fact PRL has
    hundreds of physiological functions. Was
    originally called luteotropic hormone because its
    1st known function was to promote corpus luteum
    function in rat ovary.

Salt marsh killfish
actual crop milk
crop sac
33
Anterior Pituitary hormones (cont.)
  • chromatophil secreted
  • ACTH (Adrenocorticotropic hormone) secreted by
    the chromatophils.
  • 39 amino acids 4500 daltons in weight
  • ACTH released in response to CRH from the
    hypothalamus stimulates the adrenal cortex to
    secrete mineralocorticoids and glucocorticoids
    (including cortisol, the primary glucocorticoid,
    which may feed back to control ACTH release.
    This conclusion is based on an increase in ACTH
    secretion after adrenalectomy.)

Relationship between CRH, ACTH, and adrenals
34
Posterior Pituitary hormones
  • Two peptides, oxytocin and vasopressin, are
    released from the posterior lobe of the pituitary
    in mammals.
  • Oxytocin regulated by electrical activity of the
    oxytocin cells in the hypothalamus. Vasopressin
    secreted in response to increased osmotic
    pressure in the heart, veins, and carotid
    arteries.
  • Oxytocin (Greek quick birth) influences
    reproductive function
  • Important in birth
  • Causes uterine contractions (synthetic
    oxytoxin--Pitocin--used to induce labor)
  • Causes the letdown reflex (in response to sensory
    stimulation of the nipples, oxytocin is released,
    travels to the mammary glands, which contract
    upon exposure, causing milk letdown--and because
    of prior associations--cry of a hungry baby, or
    the sound of a milking machine (in cows) produces
    the same mechanism.
  • Behaviorally
  • oxytocin injected into the cerebrospinal fluid
    causes spontaneous erections in rats
  • In the Prairie Vole, oxytocin released into the
    brain of the female during sexual activity is
    important for forming a monogamous pair bond with
    her sexual partner
  • Sheep and rat females given oxytocin antagonists
    after giving birth do not exhibit typical
    maternal behavior. By contrast, virgin female
    sheep show maternal behavior towards foreign
    lambs upon cerebrospinal fluid infusion of
    oxytocin
  • Crossing the placenta, maternal oxytocin reaches
    the fetal brain and induces a switch in the
    action of neurotransmitter GABA from excitatory
    to inhibitory on fetal cortical neurons. This
    silences the fetal brain for the period of
    delivery and reduces its vulnerability to hypoxic
    damage
  • Vasopressin (aka antidiuretic hormone--ADH--or
    arginine vasopressin--AVP--acts to retain water
    in four-footed vertebrates.
  • Rate of filtration in the kidneys slows in
    response to ADH, resulting in water retention.
  • ADH has hypertensive effects during serious blood
    loss--blood vessels constrict in response to
    severe hemorhage, slowing blood flow.
  • Behaviorally, vasopressin seems to induce the
    male to become aggressive towards other males.

35
Review
  • Hypothalamic hormones
  • GHRH
  • GnRH
  • MSH
  • TRH
  • CRH
  • Somatostatin
  • Pituitary Hormones
  • Anterior
  • GH (GHRH)
  • FSH, LH (GnRH)
  • TSH, PRL (TRH)
  • ACTH (CRH)
  • Posterior
  • Oxytocin (hypothalamic oxytocin cells)
  • Vasopressin (aka, ADH, AVP--increases in osmotic
    pressure).

36
Some other protein hormones
37
The Thyroid hormones
  • Thyroid gland releases its hormones in response
    to TSH stimulation from the anterior pituitary
  • There are two biologically active thyroid
    hormones, both derived from a molecule called
    thyroglobulin
  • T3, also known as tri-iodothyronine and T4,
    thyroxine have three general effects
  • Increases metabolism--generally, thyroid activity
    is greater in the winter.
  • Growth and differentiation--closely related to
    actions of GH in fact, effects probably
    represent permissive actions on GH target cells
  • permissive effects occur when one hormone induces
    receptor production for a second hormone. These
    effects are common.
  • Behavioral effects--insufficient production can
    affect CNS development, causing cretinism
    insufficient production can also delay sexual
    maturation

Endemic cretinism in the Democratic Republic of
Congo. Four inhabitants aged 15-20 years a
normal male and three females with severe
longstanding hypothyroidism with dwarfism,
retarded sexual development, puffy features, dry
skin and hair and severe mental retardation
38
The GI hormones
  • Three major gastrointestinal hormones
  • Secretin
  • Released by the duodenum (1st segment of small
    intestine). Stimulates pancreas to produce water
    and bicarbonate, which aid in digestion. Also
    stimulates liver to produce bile.
  • Gastrin
  • Released by the stomach. Stimulates insulin
    release, smooth muscle contractions of gut,
    gallbladder, and uterus.
  • Cholecystokinin (CCK)
  • Released by duodenum. Causes pancreas to secrete
    digestive enzymes causes gallbladder to contract
    and release bile

39
The Pancreatic hormones
  • Insulin
  • Only known hormone in the animal kingdom that can
    lower blood sugar (many hormones act to raise
    blood glucose levels). All cells (except for CNS
    cells) have insulin receptors. When an insulin
    receptor is activated, glucose is taken up into
    the cell, used, or stored as glycogen in muscle
    or fat cells.
  • Glucagon
  • Travels to the liver, where it breaks down stored
    glycogen (glycogenolysis), serving to increase
    blood levels of glucose. It acts in opposition
    to insulin.

40
Other peptide hormones
  • Enkephalins
  • Possibly involved in the stress response
    released by the adrenal medulla
  • Inhibin
  • Blocks secretion of FSH and aromatase (an enzyme
    that converts estrogens from androgens) released
    by the gonads (testes and ovaries). See figure
    at right.
  • Activin
  • Directly stimulates aromatase activity in the
    gonads (opposite of inhibin?) released by the
    gonads
  • Relaxin
  • Softens pelvic ligaments during pregnancy to
    allow the large head of the fetus clear passage
    through the vaginal canal during birth released
    by the ovaries

Female mouse on top left is a transgenic mouse
used to explore the potential effects of excess
inhibin on the reproductive axis. The inhibin
subunit protein was overexpressed in transgenic
mice. The transgene is expressed in numerous
tissues and levels of inhibin are highly elevated
compared to control mice, leading to a decrease
in serum FSH, and an increase in testosterone and
serum LH. Activin levels are also somewhat
depressed. The female mice are subfertile and
have very small litters. This is a consequence of
decreased ovulation, probably secondary to
alterations in FSH and LH. Most interestingly,
female mice that carry this transgene develop
several unique ovarian pathologies, including
distension of the bursal sac, the presence of
large fluid-filled cysts, and the presence of
atypical follicles that contain multiple oocytes
(Figure 3).
41
The Steroid hormones
  • All steroids have a common chemical
    structure--three six-carbon rings plus one
    conjugated five carbon ring
  • The precursor to all steroid hormones is
    cholesterol (produce from acetate in the liver)
  • Recall that steroid hormones are fat-soluble and
    move easily through cell membranes (slide 25)
  • Further recall that in circulation, they must
    bind to water-soluble carrier proteins (slide 25)
  • Three major classes of steroid hormones
  • Progestins/Corticoids
  • Androgens
  • Estrogens

cholesterol
42
The C21 steroids Progestin Corticoids
  • Two types of C21 hormones--progestins and
    corticoids
  • In response to anterior pituitary signals,
    cholesterol is converted into various steroid
    hormones in the adrenals
  • P450-linked side chain cleaving enzyme, or
    desmolase cuts cholesterol down into
    pregnenolone, which is a progestin and is the
    precursor to all other steroid hormones
  • Pregnenolone is a prohormone.
  • A prohormone is a substance that can act as a
    hormone and can be converted into another hormone
    with different endocrine properties
  • Progestins are named for their pregnancy-maintaini
    ng effects. Progesterone is important in
    maintaining pregnancy and in the initiation and
    cessation of mating behaviors (also, perhaps
    attachment)
  • Two types of corticoids glucocorticoids and
    mineralocorticoids
  • The glucocorticoids are involved in carbohydrate
    metabolism and are released under stress the two
    primary are corticosterone and cortisol. All
    reptiles and birds, as well as rats and mice
    secrete corticosterone the primary
    glucocorticoid in primates is cortisol
  • Aldosterone is the most important
    mineralocorticoid. Primarily responsible for
    retaining sodium and excreting potassium

43
The C19 steroids The Androgens
  • Progestins are precursors to all androgens.
  • Enyzmes found in the gonads convert pregnenolone
    to several different androgens (from Greek andros
    for man).
  • Most biologically important are testosterone,
    androstendione, and dihydrotestosterone (DHT)
  • Produced in the Leydig cells of the testes
    Sertoli cells are source of the androgen-binding
    proteins that carry androgens through the blood
  • Another androgen, DHEA (and DHEA-S) are produced
    in the adrenal cortex.
  • Relatively weak
  • Physio functions unknown
  • DHEA replacement may ameliorate certain aging
    effects (increased muscle mass, decreased fat
    mass)
  • Physiological functions of androgens
  • Spermatogenosis
  • Maintenance of the genital tract
  • Maintenance of the accessory sex organs (prostate
    et al.)
  • Secondary sex characteristics (body hair in
    humans, comb size in roosters, antler growth in
    deer)
  • Behavioral functions
  • Courtship
  • Copulation
  • Aggression
  • Dominance
  • Many other social behaviors (just beginning to be
    discovered)

44
The C18 steroids The Estrogens
  • Androgens are the precursors of all estrogens
    just as progestins are the precursors of all
    androgens
  • Estrogen means producing (coined 1927)
  • Enzymes in the ovaries convert testosterone and
    androstendione to estrogen by a process called
    aromatization (because removal of the 19th carbon
    results in an aromatic compound).
  • Biologically significant estrogens are estradiol,
    estrone, and estriol.
  • Note that the ovaries produce androgens, which
    are then aromatized into estrogens.
  • Sometimes excess androgens are produced or
    insufficient enzymes are present and the female
    is masculinized.
  • Conversely, if high levels of enzymes that
    convert androgens to estrogens are present in the
    testes, then estrogens will be secreted into the
    blood and the male will be feminized. DHT cannot
    be aromatized (why is this important?)
  • Physiolgical functions
  • Initiate corpora lutea formation
  • Uterine mass density (estrogen levels positively
    correlated with . . .)
  • Development of secondary sex characteristics
  • Metabolic functions
  • Water retention
  • Calcium metabolism (bone mass increases in the
    presence of estrogen)
  • Behavioral functions
  • Very important in maternal aggression and sexual
    behavior (e.g., in combination with progesterone,
    prolactin, oxytocin, estradiol induces rats to
    behave maternally in the presence of pups).
  • Progesterone is primary in maternal aggression,
    but estrogens may play a role. Maternal
    aggression in women has not been studied. Many
    other social behaviors (just beginning to be
    discovered)

45
Androgens Estrogens are not sex-linked
  • All males produce estrogens and progestins
  • All females produce androgens
  • The sex difference in circulating hormone levels
    is due to levels of gonadal enzymes.
  • Testes have more enzymes for making androgens and
    less aromatase than do ovaries
  • Ovaries produce high concentrations of androgens
    but these are easily aromatized into estrogens in
    the ovaries. These can be converted back into
    androgens, but this is an energetically expensive
    reaction
  • Recall that the adrenals produce sex hormones
  • Gene mutation(s) can lead to enzyme deficiencies
    which in turn can lead to an ovary or adrenal
    gland producing large quantities of androgens.
    See example at right

Congenital andrenal hyperplasia (lacking the
enzyme to metabolize cortisol and aldosterone,
and as a result, produce too much androgen. This
is a female with an extremely virilized clitoris.
46
Review
FYI, no such medically recognized condition as
adrenal fatigue.
47
The monoamines
  • Derived from a single amino acid
  • Two classes
  • Catecholamines
  • Indole amines
  • Adrenal medulla monoamines
  • epinephrine
  • norepinephrine
  • dopamine
  • All derived from Tryosine
  • Released in response to sympathetic neural
    signals (evoked by stress, exercise, low temp,
    anxiety, emotionality, and hemorrhage). In
    humans, norepi and epi are released at a ratio of
    14
  • Actions
  • Increase heart rate
  • Vasoconstriction of deep arteries and veins
  • Dilation of skeletal and liver blood vessels
  • Increased glycolysis
  • Increased blood glucagon concentrations and
    decreased insulin secretion
  • Pineal gland indole amines
  • Serotonin (5-HT)
  • Melatonin

The brains of baby rhesus monkeys who endured
high rates of maternal rejection and mild abuse
in their first month of life produced less
serotonin. Low levels of serotonin are linked to
anxiety and depression and impulsive aggression
in both humans and monkeys.
48
Regulation
  • Negative feedback
  • Example
  • GnRH is released from hypothalamus
  • Gonadotropins are released from anterior
    pituitary
  • Steroid and gamete production in gonads is
    stimulated
  • Resulting steroid hormones turn off GnRH
    production in the hypothalamus, which shuts down
    gonadotropin release
  • Up-regulation
  • Increase in PRL stimulates production of more PRL
    receptors
  • Back to point raised on Slide 11 (many hormones
    have a long latency of action ). Up-regulation is
    the result of protein synthesis, and can take
    weeks for the necessary quantity of receptors to
    accommodate to the higher hormone levels (case in
    point--action of certain anti-depressives require
    a substantial increase in of receptors to show
    effects must wait on receptor synthesis).
  • This point also explains the failure of
    short-term hormone experiments (insufficient
    receptors to accommodate the sudden supra-physio
    hormone load).
  • Down-regulation
  • High insulin concentrations reduce the number of
    insulin receptors

49
So, WHY should social-personality psychologists
study hormones?
  • Tiny handful of folks doing this stuff
  • Upside potential is unlimited
  • Grant is untapped
  • Prostate cancer example
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