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Hormone Physiology

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Title: Hormone Physiology


1
Hormone Physiology
  • Carey Witkov

2
  • Part I Introduction
  • Part II Feedback Loops in Hormone Control
    Systems
  • Part III Mathematical Modeling of Hormone
    Control Systems A Case Study

3
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.

4
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.

5
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.

6
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

7
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.

8
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.

9
Hormones and their sources I
  • Hypothalamus
  • thyrotropin-releasing hormone (TRH)
  • gonadotropin-releasing hormone (GnRH)
  • growth hormone-releasing hormone (GHRH)
  • corticotropin-releasing hormone (CRH)
  • somatostatin

10
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)

11
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)

12
Hormones and their sources IV
  • stomach and intestines
  • gastrin
  • secretin
  • cholecystokinin (CCK)
  • somatostatin
  • neuropeptide Y
  • liver
  • insulin-like growth factor
  • angiotensinogen
  • thrombopoietin

13
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)

14
Hormones and their sources VI
  • kidney
  • renin
  • erythropoietin (EPO)
  • calcitriol
  • skin
  • calciferol (vitamin D3)
  • adipose tissue
  • leptin

15
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)

16
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

17
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.

18
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.

19
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.

20
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.

21
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).

22
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.

23
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.

24
Compartment Model of the Testosterone Control
System
Pituitary (LH)
Testes (testosterone)
Hypothalamus (LHRH)
25
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
26
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).

27
Figure 1. Limit Cycle oscillation of testosterone
28
Figure 2. Oscillations of testosterone in man
29
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.
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