Sex Hormone Binding Globulin:

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Sex Hormone Binding Globulin
Important Regulatory Protein
or
Something your girlfriend wont do unless shes
drunk
Zach Simmons
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SHBG what is it

• Also known as TeBG, ABP, SBP and more...
• 373 aa protein
• Typically found in the blood as a homodimer
• Half-life of about 6-7 days in circulation
• Thought to be synthesized primarily in the liver
  and the sertoli cells of the testis
• Some debate as to whether these sites really
  produced identical proteins (as there may be
  differences in exon splicing depending on region)
• Enjoys long walks on the beach

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SHBG what does it do

• Binds sex-steroids!
• Specifically, 17ß-hydroxy steroids DHT,
  testosterone, and estradiol
• Binding affinities 10-9 M for DHT (thats
  strong)
• DHT gtgtgt T gtgtgt E
• 6x 2x 1x
• Has only one binding site per molecule of SHBG
• Half-life of SHBG/DHT complex 30-60 mins
• So what does this mean for sex steroids in the
  blood?

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SHBG what does it do

• First, story gets more complicated
• SHBG not the only protein in blood that binds
  steroid hormones other primary binding protein
  is albumin
• Binds steroid hormones much more weakly (binding
  affinities 10-4 M), but is much more
  plentiful in serum
• So proportion of steroid hormones that are bound
  is a function of binding to both SHGB and albumin
• Distribution of hormones between SHBG, albumin,
  and those that are free in serum dictated by
  binding affinities
• Though less SHBG, a higher percentage of it will
  be bound with hormones due to its higher affinity

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SHBG what does it do

• How the math works out

Very little hormone is actually free in
serum most is bound to either albumin or SHBG
Selby, 1990
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SHBG what does it do

• Most DHT and T is bound to SHBG, with most E
  bound to albumin

Moore Bulbrook, 1988
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SHBG what does it do

• An alternate way to think about bound fractions
  is to consider how the proportion bound to
  albumin changes in response to different levels
  of SHBG
• Remember, SHBG has the higher affinity, so it
  will dominate when present

Notice relative proportions bound remain
consistent
Moore Bulbrook, 1988
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SHBG what does it do

• So why is this important to clinical/psychological
  research?
• Have to consider fractions of free hormones vs
  total hormones when thinking about endocrine
  calibration of cognitive (neural) machinery

Notice that this pattern is quite unlike that of
absolute T
Free T throughout the day
Plymate et al., 1989
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SHBG - regulation

• Variety of factors have been shown (with mixed
  replicability) to influence SHBG levels in plasma
• Generally, estrogens produce increases
• Androgens (perhaps only high-dose) produce
  decreases
• Glucocorticoids produce decreases
• Insulin produces decreases

Botwood et al., 1995
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SHBG - regulation

• SHBG typically elevated with low body weight
  (anorexics) and suppressed with high body weight
  (obese)
• So in anorexics, steroid hormones typically bound
  to SHBG and not free (amenorrhea, anovulatory
  cycling)
• In obese, excess of steroid hormones free in
  circulation (androgenization, hirsutism)
• Effects on SHBG can typically be reversed with
  changes in diet (energy balance)
• SHBG levels generally rebound to normal levels
  before reproductive function

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SHBG - regulation

• Obese patients show SHBG recovery after both
  short- and long-term dieting

Franks et al., 1991
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SHBG what is its function

• Relatively clear what it actually does, but that
  does not explain its function
• Why produce a bunch of sex steroids, just to have
  most of them be sequestered by another protein
  (that also has to be produced)?
• Wasteful system, unless it does something else
• So why have it at all? Why not just produce
  fewer sex steroids and eliminate the need for
  SHGB altogether?

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SHBG what is its function

• Three primary hypotheses have been advanced
• The free hormone hypothesis, which states that
  only unbound hormones are biologically active, so
  SHBG must have a role in regulating levels of
  free hormone
• The cell surface receptor hypothesis, which
  states that there are receptors on cells for
  SHBG, and that these receptors respond to SHBG
  and hormones through some unspecified process
  (endocytosis of protein/hormone complex, second
  messenger systems, etc)
• The oops, I got out of the cell hypotheses, so
  named because it didnt have a name. Essentially
  posits that SHBG was actually designed for
  intracellular use, and plasma levels are just
  leakage or noise. Ok, lets call it the
  by-product hypothesis.

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SHBG free hormone hypothesis

• Holds that the only bioactive steroid hormones
  are those that are unbound
• Actually, slightly more complex in that binding
  to albumin doesnt count (because of its low
  affinity, it readily releases hormone)
• In this model, SHBG acts to decrease bioavailable
  hormone
• Seems counterproductive, but at the same time it
  increases the metabolic clearance rate (MRC) of
  sex steroids
• MCR is just a measure of how long it takes the
  body to break down a substance, so a high MCR
  indicates that a substance takes longer to break
  down
• In this way, SHBG acts as a buffer it sequesters
  some hormone and then slowly releases it so that
• More hormone is released as existing free
  hormones are metabolized
• Bioavailable hormone levels are smoothed out,
  relative to the pulses in which they are released

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SHGB free hormone hypothesis

• Shown clearly in rats (which do not have SHBG,
  but a variant called ABP produced exclusively in
  sertoli cells)

Previously added human SHBG to rats
Activity recovered when rabbit SHBG added
(anti-hSHBG is not effective)
Entirely blocks effects of SHBG on MCR of T
Stanczyk et al., 1986
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SHGB free hormone hypothesis

• Corollary is that hormones enter tissues more
  gradually (as they are sequestered and released)
• Does not predict differences in equilibrium
  concentrations in tissues, just that equilibrium
  achieved more slowly

SHBG increases time taken to hit equilibrium
levels of T in CSF albumin does not
Hobbs et al., 1992
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SHBG cell receptor hypothesis

• Some evidence that certain types of cells have
  receptors for SHBG
• Complex, because different tissues may have
  receptors that work in different ways
• In some, evidence that SHBG/hormone complex is
  moved into the cell via endocytosis, where
  hormone dissociates
• In others, evidence that SHBG binds to surface of
  cells only when it has not bound hormone, and
  once there can bind circulating hormones, which
  triggers 2nd messenger cascade
• Still others suggest that perhaps the
  SHBG/hormone complex binds on the cell surface,
  but the hormone immediately dissociates and moves
  into the cell via diffusion
• The point its complicated, and there is
  certainly no consensus as to how things work (or
  whether they work in more than one way)

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SHBG cell receptor hypothesis

• One possible model of SHBG binding to cell
  surface only when hormone not present

Must bind to cell before binding hormone
Hyrb et al., 1990
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SHBG cell receptor hypothesis

• And another for moving into the cell when bound
  to hormone

Note that hormone binding occurs
before interacting with cell receptor
Munell et al., 2002
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SHBG cell receptor hypothesis

• But why bother?
• May allow for concentrations in certain tissues
  (with receptors) to be much higher than diffusion
  gradients would allow
• Some argue that this must necessarily be the case
  (as nuclear receptors require concentrations
  greater than those achieved by simple diffusion
  to be efficient) but there are counterarguments
  (based on local diffusion microgradients)
• If some receptors are specific to SHBG complexed
  to particular hormones, would allow for
  concentrations of those hormones to be targeted
  to tissues

Pardridge, 1988
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SHBG the by-product hypothesis

• No graphs, no figures, no charts
• Why? Because its crazy
• But it is admirable for thinking outside the box
• Might be plausible that binding protein did
  develop to sequester hormones inside the cell (to
  prevent metabolizing them, to target them to
  organelles)
• But this does nothing to explain the tremendous
  levels seen in the blood, as well as the precise
  (though still somewhat mysterious) mechanisms by
  which SHBG levels are regulated

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SHBG conclusions

• Pretty confident that it binds steroid hormones
• Far less confident as to why
• Free hormone hypothesis seems somewhat plausible,
  but is not entirely convincing
• If the point is to act as a buffer, why are
  circulating hormone levels still so strongly
  pulsatile, and why are dirunal variations still
  seen
• Cell receptor hypothesis is also somewhat
  plausible, but a lot more details need to be
  filled in before it can be critically evaluated
• Since SHBG does not seem to be obligate in many
  (most? all?) cases for function, what added
  benefit would a receptor system provide?
• By-product hypothesis to review crazy.

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SHBG final thoughts

• One interesting consideration is that if
  androgens suppress SHBG action, and low levels of
  SHBG result in higher levels of circulating
  endogenous testosterone, one might predict that
  people who abuse androgens might actually be
  encouraging a kind of positive feedback that
  would flood their bodies with testosterone,
  resulting in grotesque abnormalities

Im just grateful science could never help create
such a monster
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Acknowledgments

• Labatt Brewing Company
• The internet
• My hero, Dan Scanchez
• Kevin Lominac, for graciously not knowing enough
  about the internet to keep his photos off of it
• A.C. (Slater)
• All the little people out there