Steroid Hormones: Organization versus Activation

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Steroid Hormones Organization versus Activation

• Lique Coolen
• Department of Anatomy Cell Biology Physiology
  Pharmacology

Micahs 1st Halloween
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Hormones

• Classic definition
• Chemical products secreted into the blood that
  act on distant tissues, usually in a regulatory
  fashion.
• Hormones can be released from endocrine and
  non-endocrine organs eg., the heart
• Hormone Effects
• Endocrine
• Paracrine
• Autocrine
• Intracrine

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Gonadotropin Releasing Hormone (GnRH)

• GnRH was discovered independently by Drs. Roger
  Guillemin and Andrew V. Schally
• Nobel Prize in Medicine in 1977 for their
  independent work that led to the isolation of
  hormones from the brain region known as the
  hypothalamus
• Mammalian GnRH, termed GnRH-I (Glu-His-Trp-Ser-Ty
  r-Gly-Leu-Arg-Pro-Gly) is a key regulator of the
  reproductive axis in diverse vertebrates.
• A second GnRH subtype, termed GnRH-II, originally
  identified from chicken hypothalamus has been
  found in humans.
• This second GnRH form differs from GnRH-I by
  three amino acid residues at positions 5, 7, and
  8 (His5Trp7Tyr8GnRH-I).

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The Hypothalamus
The hypothalamus is located at the base of the
forebrain and regulates homeostatis
metabolic/autonomic activities such as food
intake, energy expenditure, body weight, fluid
intake and balance, thirst, blood pressure, body
temperature, sleep cycle, and reproduction.
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The location of GnRH neurons is
species-dependent Primates in preoptic area,
anterior hypothalamic area, and the medial
basal Rodents only in rostral areas- the
preoptic area, and anterior hypothalamus
GnRH neurons are relatively few in number,
diffusely distributed in the POA and are not
organized into nuclei
GnRH neurons in the mouse and rat
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The Pituitary Gland The pituitary gland,
or hypophysis, the size of a pea sits in a small,
bony cavity (sella turcica) at the base of the
brain and is functionally connected to the
hypothalamus Hypothalamus releases hormones into
the pituitary (including GnRH)
The posterior pituitary lobe (neurohypophysis) is
directly connected to the brain and is derived
from the neural ectoderm. The anterior
(adenohypophysis) and intermediate lobes are
derived from the oral ectoderm (FYI In humans
the intermediate lobe is a thin layer of cells
between the anterior and posterior lobes)
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The Hypothalamus-Pituitary
Hypothalamic neuroendocrine neurons are comprised
of two types of neurons that mediate hypothalamic
endocrine functions Magnocellular and
Parvicellular Neurons

Parvicellular neurons (hypophysiotropic cells)
extend into the ME where they release their
neuropeptides into the anterior pituitary, via
the portal circulation, where they increase or
decrease synthesis and release of other hormones
from the anterior pituitary into the general
circulation (example GnRH)
Magnocellular neurons (neurohypophyseal cells),
whose axons traverse the ME, extend directly into
the posterior pituitary and release their
neuropeptides that are then released directly
into the general circulation.
oxytocin and vasopressin gonadotropin
releasing hormone (GnRH) corticotropin
releasing hormone (CRH or CRF) thyroid
stimulating hormone releasing hormone (TRH)
growth hormone releasing hormone (GHRH)
somatostatin / growth hormone inhibiting hormone
(GHIH)
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Magnocellular neurosecretory neurons
Neurohypophysis Posterior pituitary
Adenohypophysis Anterior pituitary
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Hypothalamus-Pituitary
The hypothalamus releases hormones such as GnRH
into the anterior pituitary via a bridgelike
structure, the median eminence (ME). ME is one
of seven areas of the brain devoid of a
blood-brain barrier (BBB) and where axon
terminals of hypothalamic neurons release
(hypophysiotropic) neuropeptides involved in the
control of anterior pituitary function. The ME
is also traversed by the axons of hypothalamic
neurons ending in the posterior pituitary
Anterior Pituitary
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GnRH neurons
GnRH neurons
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Hypothalamus-Pituitary
The Hypophysial Portal Vascular System

• Hypophysiotropic peptides (eg, GnRH) released
  into the ME from hypothalamic nerve endings
• They enter the 1o plexus capillaries (which
  receives blood from the carotid artery)
• Transported to anterior pituitary via
  hypophysial portal veins (long parallel portal
  veins connect two capillary beds) located in the
  pituitary stalk
• into the 2o plexus which supplies blood to the
  anterior pituitary
• peptides exit the 2o plexus and act on receptors
  (eg, GnRH-R) on anterior pituitary cells
  regulating hormone production/secretion
• These hormones then enter the same capillaries
  and are carried into the general circulation.
  Luteinizing Hormone and Follicle Stimulating
  Hormone (LH and FSH)

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GnRH acts on pituitary to release LH and FSH
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Hypothalamic-Pituitary-Gonadal AxisHPG-Axis
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HYPOTHALAMIC-PITUITARY-GONADAL AXIS
Feedback by Steroid Hormones Estrogen Produced
by granulosa cells/developing follicles Progestero
ne secreted from the developing corpora
lutea (Testosterone) Negative or Positive
Feedback
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Cycles Human
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GnRH
Feedback Regulation
1 LH pulse/60 mins
1 LH pulse/90 mins
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Early in Follicular Phase Estradiol is secreted
by developing follicles, therefore estradiol is
low. Correspondingly, there is a weak
estradiol-induced inhibition of the GnRH pulse
generator and LH pulse frequency is relatively
fast at 1 pulse/60 mins.
1 LH pulse/60 mins
1 LH pulse/90 mins
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Late Follicular Phase As estradiol level builds
up as follicular phase progresses, a stronger
negative estradiol-induced regulatory feedback on
the GnRH pulse generator is observed leading to a
reduced LH pulse frequency of 1 pulse/90 mins
1 LH pulse/90 mins
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Preovulatory GnRH/LH-Surge However, as more
estradiol is produced (see pre-ovulatory peak), a
level is achieved that leads to a positive
estradiol-induced feedback on the GnRH pulse
generator and the surge release of LH and FSH and
ovum release
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The luteal phase the empty follicle transformed
into the corpus luteum. This becomes a rich
source of progesterone (and some estradiol).
This maintains pregnancy and together strongly
negatively feeds back on the GnRH pulse generator.
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Species Differences
Primate and Sheep similar to Human
Rodents lack long luteal phase Progesterone has
positive feedback on preovulatory surge
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Steroid Feedback on GnRH neurons

• GnRH neurons lack receptors for estradiol (ER
  alpha) and progesterone
• some contain ER beta, but this receptor is not
  involved with estradiol-feedback on GnRH neurons
• So, steroids provide feedback on GnRH system
  indirectly via interneurons

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Regulation of GnRH neurons

• Much research is ongoing to further delineate the
  functional network that controls GnRH neurons
• Numerous neuro- transmitters and peptides have
  been identified to regulate GnRH (gt35)
• Kisspeptin is a major modulator

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Steroids act during different times of life

• Steroid feedback of GnRH secretion in adulthood
• Activational effects
• Steroids act on GnRH system during puberty
• Steroids act during early/prenatal life
• Organizational effects cause permanent changes
  to reproductive (and other systems)

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Sexual differentiation of gonads
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SEXUAL DIMORPHISM

• Prenatal steroids play critical role in sexual
  differentiation of brain and behavior
• A wide range of animal and human behaviors are
  sexually dimorphic (dimorphic means two forms).
  
• Some of these behaviors are reflexive in nature
  (reproduction), others require a high level of
  cognitive activity (spatial thinking, language).

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SEXUAL DIMORPHISM OF BRAIN
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DIFFERENTIATION OF THE BRAINTHE ACTIVE AGENT IS
ESTRADIOL

• Testosterone is converted to estradiol once it
  has entered the relevant neurons (enzyme that
  converts testosterone to estradiol aromatase).
• Thus, it is estradiol/estrogen that acts inside
  neurons to stimulate sexually dimorphic patterns
  of neuronal circuitry as a result of the presence
  of testosterone in developing males.
• Organizational effects of estradiol
• Humans prenatal
• Rodents perinatal (first week after birth)

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TROPHIC EFFECT OF ESTROGEN(DOMINIQUE
TORAN-ALLERAND, 1978)
No estrogen
Estrogen
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ESTROGEN TROPHIC FACTOR

• Estradiol can produce brain dimorphisms by
• increasing neuronal size
• nuclear volume
• (size of brain area)
• dendritic length
• dendritic branching
• spine density
• and number of synapses

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EXAMPLES OF SEXUALLY DIMORPHIC BRAIN
AREASHYPOTHALAMUS

• the sexual dimorphic nucleus (SDN Roger Gorski
  and coworkers, 1978)
• SDN is small in females and large in males, and
  its development is under the influence of
  estradiol.

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RAT SDN
Male
Female
Female Testosterone
Female Estrogen
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• Since then, other sexual dimorphic nuclei in
  hypothalamus have been described, as well as in
  amygdala, brainstem, spinal cord, cortex.
• Generally, these nuclei are larger in males than
  in females.

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FUNCTION OF BRAIN SEXUAL DIMORPHISM?

• Sexually dimorphism in reproductive function
• Female ovulation
• Reproductive behavior
• Female feminine sex behavior maternal behavior
• Male masculine sex behavior, requires
  defeminization and masculinization of behavior
  aggression
• Cognition and language
• Disease onset and progression

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Cell-autonomous action of sex-chromosome genes

• Recent studies in rodents and birds have
  demonstrated that sexual differentiation can
  occur independent of gonadal hormones and involve
  sex chromosome genes
• gynandromorph

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Zebra finch gynandromorph
Female ZZ
Male ZW
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Thank you

• Have lots of fun this week!