Hormone Physiology

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Hormone Physiology

• Carey Witkov

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• Part I Introduction
• Part II Feedback Loops in Hormone Control
  Systems
• Part III Mathematical Modeling of Hormone
  Control Systems A Case Study

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Part I Introduction

• Overview
• Hormone physiology encompasses some of the most
  important control mechanisms in the human body,
  including control of blood sugar (insulin),
  control of the fight or flight response
  (epinephrine), control of metabolism (thyroxine)
  control of the female ovulatory cycle and control
  of the male spermatogenesis process.

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What is a Hormone?

• Dictionary Definition
• A substance, originating in an organ, gland, or
  body part that is conveyed through the blood to
  another body part, chemically stimulating that
  part to increase or decrease functional activity
  or to increase or decrease secretion of another
  hormone.
• -- Tabers Cyclopedic Medical Dictionary, 18th
  edition, Philadelphia F.A. Davis Company, 1997.

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What is a Hormone?

• Operational definition
• Hormones are signaling molecules that control
  cellular and organ functions via feedback loops.
  Approximately 50 hormones are synthesized in
  about a dozen glands and other tissues,
  transported by the bloodstream or released into
  the interstitial fluid, and bind to receptors on
  target cells.

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Types of Hormones Classification by Mode of
Signaling

• Endocrine and neurosecretory hormones
• Synthesized in endocrine gland cells and in the
  hypothalamus and released into the bloodstream
• Paracrine, autocrine, synaptic
• Paracrine released into interstitial fluid
• Autocrine affect the cells that secrete them
• Synaptic affect signaling between neuron and
  neuron or neutron and muscle

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Types of Hormones Classification by Structure

• Steroids
• fat-soluble molecules made from cholesterol
  (e.g., gonadotropins estrogens, androgens and
  progesterones).
• pass into a cell's nucleus, bind to specific
  receptors and genes and trigger the cell to make
  proteins.
• Amino acid derivatives
• water-soluble molecules (e.g., epinephrine)
  derived from amino acids.
• stored in endocrine cells until needed.
• bind to protein receptors on the outside surface
  of the cell.
• alert a second messenger molecule inside the cell
  that activates enzymes and other cellular
  proteins or influences gene expression.
• Peptide hormones
• water-soluble polypeptide hormones (e.g.,
  insulin, growth hormone, prolactin) are long
  chain amino acids.
• stored in endocrine cells until needed to
  regulate such processes as metabolism, lactation,
  growth and reproduction.

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Hormones and their sources

• To help place into perspective the scope of the
  system of hormones in the human body, the next
  seven slides are a reference to the major
  hormones and the sites where they are generated.

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Hormones and their sources I

• Hypothalamus
• thyrotropin-releasing hormone (TRH)
• gonadotropin-releasing hormone (GnRH)
• growth hormone-releasing hormone (GHRH)
• corticotropin-releasing hormone (CRH)
• somatostatin

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Hormones and their sources II

• Pituitary gland
• anterior lobe (adenohypophysis)
• GH (human growth hormone)
• PRL (prolactin)
• ACTH (adrenocorticotropic hormone)
• TSH (thyroid-stimulating hormone)
• FSH (follicle-stimulating hormone)
• LH (luteinizing hormone)
• posterior lobe (neurohypophysis)
• oxytocin
• ADH (antidiuretic hormone)

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Hormones and their sources III

• pineal gland
• melatonin
• thyroid gland
• thyroxine (T4)
• triiodothyronine (T3)
• calcitonin
• parathyroid glands
• parathyroid hormone (PTH)
• heart
• atrial-natriuretic peptide (ANP)

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Hormones and their sources IV

• stomach and intestines
• gastrin
• secretin
• cholecystokinin (CCK)
• somatostatin
• neuropeptide Y
• liver
• insulin-like growth factor
• angiotensinogen
• thrombopoietin

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Hormones and their sources V

• islets of Langerhans in the pancreas
• insulin
• glucagon
• somatostatin
• adrenal glands
• adrenal cortex
• glucocorticoid- cortisol
• mineralocorticoid - aldosterone
• androgen (including testosterone)
• adrenal medulla
• adrenaline (epinephrine)
• noradrenaline (norepinephrine)

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Hormones and their sources VI

• kidney
• renin
• erythropoietin (EPO)
• calcitriol
• skin
• calciferol (vitamin D3)
• adipose tissue
• leptin

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Hormones and their sources VII

• In males only
• testes
• androgens (testosterone)
• In females only
• ovarian follicle
• oestrogens
• testosterone
• corpus luteum
• progesterone
• placenta (when pregnant)
• progesterone
• human chorionic gonadotrophin (HCG)

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Part II Feedback Loops in Hormonal Control
Systems

• Owing to the complex interactions among various
  hormones it is useful to characterize many of the
  feedback loops by the principal glands involved.
  The main glandular axes are
• Hypothalamus -- Pituitary -- Ovarian Axis
• Hypothalamus -- Pituitary -- Adrenal Axis
• Hypothalamus -- Pituitary -- Thyroid Axis
• Hypothalamus -- Pituitary -- Testicular Axis
• Hypothalamus Adrenal -- Pancreas Axis

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Hypothalamus -- Pituitary Ovarian Axis

• Gonadotropin-releasing hormone (GnRH),released
  from the hypothalamus to the pituitary,
  stimulates release of follicle-stimulating
  hormone (FSH) and luteinizing hormone (LH).
• FSH and LH stimulate the follicle to produce
  estrogen. 
• Estrogen levels rise, inhibiting synthesis of FSH
  and LH.
• Estrogen levels continue to rise to a threshold
  which reverses the negative feedback and LH
  surges.  
• Ovulation occurs after the LH surge damaging the
  estrogen-producing cells which lowers estrogen
  levels.  
• The LH surge results in the formation of the
  corpus luteum -- an estrogen and progesterone
  secreting gland.   
• Estrogen and progesterone serum levels rise,
  supressing LH output. 
• Lack of LH promotes the degeneration of the
  corpus luteum.
• Cessation of corpus luteum activity causes a
  reduction in estrogen and progesterone levels. 
• Reduced levels of ovarian hormones stops their
  negative effect on the secretion of LH.  
• LH is secreted and the cycle begins again.

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Hypothalamus -- Pituitary -- Adrenal Axis

• The adrenal cortex produces cortisol in response
  to corticotropin (ACTH, adrenocorticotropic
  hormone) produced by the pituitary gland. The
  corticotroph cells in the pituitary gland sense
  the blood levels of cortisol. If cortisol levels
  are too low, more ACTH is secreted.
• The hypothalamus controls the rate at which the
  corticotroph cells respond. Hypothalamus control
  is influenced by stress and the CRH
  (Corticotropin-releasing hormone) pulse rate
  which, in turn, is affected by systemic
  inflammation.
• Cortisol inhibits secretion of CRH, resulting in
  feedback inhibition of ACTH secretion.

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Hypothalamus -- Pituitary -- Thyroid Axis

• The thyroid gland synthesizes thyroxine (T4) and
  triiodothyronine (T3)  in the presence of iodide.
• Low levels of thyroid hormones in the blood are
  detected by the hypothalamus and the pituitary.
• TRH is synthesized in the hypothalamus and
  stimulates the pituitary to release TSH.
• TSH is synthesized in the pituitary and
  stimulates the thyroid to produce T3 and T4.

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Hypothalamus -- Pituitary -- Testicular Axis

• Gonadotropin-releasing hormone (GnRH) is
  synthesized in the hypothalamus.
• GnRH stimulates the pituitary to synthesize two
  gonadotropins, follicle-stimulating hormone (FSH)
  and luteinizing hormone (LH).
• LH stimulates testosterone synthesis.
• Testosterone levels are controlled by negative
  feedback, i.e., teststerone inhibits secretion of
  GnRH and LH.

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Hypothalamus Adrenal Pancreas Axis (blood
glucose regulation)

• Increasing blood glucose levels acts on the
  islets of Langerhans of the pancreas to increase
  secretion of insulin.
• Increased insulin secretion causes cells of the
  body to become more permeable to glucose.
• Glucose is transported into cells and the blood
  glucose level falls.
• Low blood sugar excites the sympathetic
  hypothalamic nuclei to cause epinephrine and
  norepinephrine release.
• Epinephrine acts on liver cells to increase the
  rate of glucose production (glycogenolysis).

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Part III Mathematical Modeling of Hormone
Control Systems A Case Study

• Realistic mathematical modeling of hormone
  control systems is more difficult than that of
  other biological control systems for several
  reasons
• Multiplicity of hormonal feedback loops.
• More difficult to measure hormone levels than
  voltage levels.
• Distance between the site of synthesis and the
  site of action with attendant complexities
  associated with transport.
• The above arguments were made in James Keener and
  James Sneyd, Mathematical Physiology, Springer
  1998.

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A Mathematical Model of Control of Testosterone
Production

• This model is considered in Mathematical Biology
  by James Murray (Berlin Springer-Verlag). It is
  a particularly interesting model as it exhibits a
  limit cycle.
• Hormones used in the model.
• LHRH
• Luteinizing Hormone Release Hormone, secreted by
  the hypothalmus
• LH
• Luteinizing Hormone, released by the pituitary
  and controlled by LHRH
• T
• testosterone, produced in the testes and
  controlled by LH.

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Compartment Model of the Testosterone Control
System
Pituitary (LH)
Testes (testosterone)
Hypothalamus (LHRH)
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The model
R LHRH L LH T Testosterone The parameters a,
b, c, d and e are given the value 1 while V is
set to 1, K 0.1 and m 9. Testosterone
inhibits secretion of LHRH using nonlinear
feedback. This particular model originates from
the Hill equation. In this case it is a
positive, monotonic, decreasing Hill equation.
R
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Matlab files

• Two matlab files to simulate James Murrays model
  were created by Natal van Riel from the
  Technische Universiteit Eindhoven. These are
• testosterone_osc.m
• testosterone_osc_ode.m
• Running these files with the parameter values
  given in the model result in two plots
• A limit cycle oscillation of testosterone versus
  LHRH (figure 1)
• A time-series plot of testosterone, LH, and LHRH
  oscillations (figure 2).

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Figure 1. Limit Cycle oscillation of testosterone
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Figure 2. Oscillations of testosterone in man
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Discussion

• Figure 1 shows a testosterone limit cycle
  oscillation. Limit cycles are widely found in
  biological systems as they are robust in
  maintaining oscillations independent of external
  disturbances.
• Figure 2 shows 5 pulses/day. Table 19.1 in Keener
  and Sneyd (op. cit) cites studies showing 8-13
  pulses/day. Thus the model with the values used
  underpredicts the number of daily testosterone
  pulses.
• Figure 2 shows an initial peak testosterone pulse
  with the remaining testosterone pulses smaller
  with uniform amplitude. This is consistent with
  the peak testosterone pulse occurring once per
  day in the morning. However, the simulation
  showed no recurrence of this peak over a period
  of 50 hours.