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BIOL31571 > Lecture 14 - Pathophysiology of GH/IGF axis in postnatal life II > Flashcards

Lecture 14 - Pathophysiology of GH/IGF axis in postnatal life II Flashcards

1
Q

GH/IGF abnormalities: how may they affect puberty and what treatments exist?

A

Too little – puberty delayed; common in catabolic states - GH/IGF or testosterone
Too much – puberty advanced; clinical & animal studies implicate IGF-1 - GnRH agonists/antagonists to suppress FSH/LH production

Affected characteristics:
* Height
* Genitalial development
* Secondary sexual characteristics
* Psychosocial development

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2
Q

GH/IGF abnormalities: what may they be caused by?

A
  • Genetic factors
  • Epigenetic factors?
  • Nutritional status
  • Adiposity?
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3
Q

Gonaodotrophs: what axis are they involved in and what do each stage do?

A

Hypothalamus - Gonadotrophin Releasing Hormone (GnRH)
Anterior pituitary - Gonadotrophs
Gonads - affects gametes/sex steroids

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4
Q

Puberty: by what mechanism is it initiated?

A

Pre-puberty:
* GnRH inhibited by dynorphin
* GnRH in a quiescent state (juvenile pause)

Multiple mechanisms of activating puberty:
* IGF-1 levels increase as the liver produces more (as a response to nutrition/caloric intake), activates KNDy cells
* KNDy cells produce neruokinin B which suppresses dynorphin
* Dynorphin effect is decreased
* Inhibition of GnRH neurons is stopped and GnRH is produced and secreted

  • IGF-1 levels increase, activates KNDy cells
  • KNDy cells produce kisspeptin
  • Kisspeptin activates GnRH neurones and GnRH is produced and secreted
  • IGF-1 levels increase and promote adipose tissue formation
  • Leptin is produced by adipose tissue and travels to the KNDy neuron, activating it
  • KNDy neurons activate gonadotrophin-releasing hormone (GnRH) neurons in the hypothalamus
  • Hypothalamus releases gonadotrophin-releasing hormone (GnRH)
  • IGF-1 levels increase and act on neighbouring glial cells near the GnRH neurones
  • These cells produce prostaglandin which promotes GnRH production

GnRH effects:
* GnRH causes Gn release (FSH/LH) from the anterior pituitary
* FSH/LH affect the ovaries and cause oocyte development and ovulation

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5
Q

KNDy neuron: what is it, what does it do, and what is it activated and inhibited by?

A

Kisspeptin-neurokinin-dynorphin neuron

Produces signalling molecules (dynorphin and kisspeptin/neruokinin B) which control the timing of puberty by either inhibiting or activating GnRH neurones -

  • Leptin
  • IGF-1
  • Gonadotrophins (negative feedbacl)
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6
Q

Menstrual cycle: what two parts of it are there?

A
  • Uterine cycle
  • Ovarian cycle
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7
Q

Uterine cycle

A
  • Menstrual phase - ~5 days
  • Proliferative phase - ~9 days
  • Secretory phase - ~14 days
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8
Q

Ovarian cycle

A
  • Follicular phase - ~14 days
  • Luteal phase - ~14 days
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9
Q

Dominant follicle: how is it produced?

A

One of the tertiary follicles will become the dominant follicle

IGF-1 required

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10
Q

IGF: what is it, what is its role in follicle development and ovulation, and how is it regulated?

A

Insulin-like growth factor

  • Produced as a response to estradiol production
  • Stimulates steroidogenesis - directly and also by augmenting gonadotropin action
  • Stimulate granulose cell proliferation and survival

IGFBPs

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11
Q

Follicular development: what causes it to occur, and what are the stages?

A

Gonadotrophin-dependent initially

  • Primordial follicles
  • Primary follicles
  • Secondary follicles
  • Tertiary follicles
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12
Q

Primordial follicles: what are they, what stage of meiosis development are the oocytes in, and what are their granulosa cells like?

A

Structure containing an immature oocyte and a layer of granulosa cells

1st meiotic prophase

Single-layer, flat

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13
Q

Primary follicles: what are they, what are their key features, what stage of meiosis development are the oocytes in, and what are their granulosa cells like?

A

Follicle containing a developing oocyte and a cuboidal layer of granulosa cells

  • FSH receptor expression
  • Oocyte growth and differentiation
  • Zona pellucida
  • Theca

1st meiotic prophase

Single-layer, cuboidal

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14
Q

Secondary follicles: what are they, what are their key features, what stage of meiosis development are the oocytes in, and what are their granulosa cells like?

A

Follicle containing a developing oocyte and a multi-layer cuboidal layer of granulosa cells

  • Oocyte growth and differentiation
  • Zona pellucida
  • Theca - internal and external
  • Follicular fluid

1st meiotic prophase

Multi-layer, cuboidal

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15
Q

Tertiary follicles: what are they, what are their key features, what stage of meiosis development are the oocytes in, and what are their granulosa cells like?

A

An ovarian follicle that has reached a late stage of development

  • Zona pellucida
  • Theca – interna & externa
  • Antral cavity
  • Sex steroids

1st meiotic prophase

Multi-layer, cuboidal

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16
Q

Granulosa cells: what are they and what do they do?

A

Cells in the ovarian follicles that support oocyte development

17
Q

Theca cells: what are they and what do they do?

A

Endocrine cells in the interfollicular stroma that affect reproduction and fertility

18
Q

IGF-I production: what gonadotroph may it be stimulated by and by what mechanism may this occur?

A

Estradiol

  • LH stimulates thecal cell
  • Thecal cell produces androgens
  • Androgens and FSH promote granulosa cells aromatise androgens to secrete estradiol-17β
  • Estradiol acts back on granulosa cells to produce IGF-I
19
Q

IGFBPs: what are they, what do they do, and what are they inhibited by?

A

IGF binding proteins

Bind to IGFs, inhibiting their activity

  • FSH - stimulates IGFBP protease activity and suppresses IGFBP production
  • Kallikreins - proteases that cleave IGFBPs
  • MMPs (matrix metalloproteases) - breaks IGFBPs down
  • PAPP-A (Pregnancy-associated plasma protein A) - cleaves IGFBPs
20
Q

How do stromal and epithelial cells communicate?

A

Originally thought to potentially be:
* Paracrine factor?
* EGF
* FGF
* TGF

Evidence suggests that it is IGF - IGF is stimulated by estrogen and results in endometrium epithelial cell proliferation

21
Q

IGF-I receptor inhibition: what causes it and what does it cause to happen?

A

PPP

Prevents estrogen-induced proliferation

22
Q

E: what is it, what does it do, and what is it inhibited by?

A

Estrogen

Stimulates IGF-1 expression in stroma

Inhibition of the IGF-1 receptor

23
Q

PPP: what is it and what does it do?

A

Picropodophyllin - an IGF-I receptor inhibitor

  • PPP (in uterine lumen) blocks E-mediated activation of IGF-1 receptor
  • PPP inhibits E-stimulated epithelial proliferation
24
Q

IGF/IGF1R and cancer: what is their relationship?

A

May promote:
* Angiogenesis
* Epithelial to mesenchymal transition (EMT)
* ECM invasion
* Immune escape
* Maintenance of cancer stem cells

High IGF levels and IGF1R activity cause a higher risk of cancer

25
Q

IGF/IGF1R and cancer: what evidence is there to support their relationship?

A

In vitro - IGF1R –ve cells resistant to transformation but growth not impaired

Animal models:
* lid mouse (reduced circulating IGF-I levels) – resistant to tumour induction
* Caloric restriction – reduced incidence and growth of various tumours
* Overexpression of IGF-1R leads to tumour formation

Epidemiological studies:
* Physicians Health & Nurses Health Studies
Measured IGF-I levels 7 or 2 years before the onset of cancer
* Risk increased (2-fold) if IGF-I level upper end of the normal range

26
Q

Acromegaly: since IGF-I overexpression causes an increased cancer risk, does this also occur in those with acromegaly?

A

Acromegaly is not associated with an increased risk of prostate/breast cancer

27
Q

IGF-I: what is the treatment of those with high levels?

A

Licenced & unlicensed use of GH & IGF-I

28
Q

Treatment with IGF-1: what are the potential issues?

A

No cases of malignancy reported to date but current data from a small population and short time frame so more follow-up needed

29
Q

GH usage: what studies have occurred to investigate the potential relationship with cancer and what was found?

A

Follow-up of children treated with GH:
* In general, no increase in cancer risk (but lifelong surveillance is necessary)
* Slight increase in risk for those with a history of malignancy

2012 – EU SAGhE study
* 1st study: increased mortality, particularly in those receiving the highest dose
* 2nd study: no deaths from cancer
* Appropriate control group in either study - not using “normal kids”, instead use GH-deficient children (a group that can’t ethically exist)?

2018 – EU SAGhE study – results inconclusive:
* Follow-up of adults treated with GH
* Not well-studied
* Available data suggests no risk

30
Q

IGF axis: is it a good target for cancer treatment, what is the mechanism behind this process, what are the existing treatments, and how promising are they?

A

Potentially

  • Down-regulate signalling through the type 1 IGF receptor
  • Decreased receptor expression
  • Decreased receptor activation

Selective tyrosine kinase inhibitors:
* Some compounds had toxicity in pre-clinical testing
* Phase I and II trials ongoing

Monoclonal antibodies:
* Block ligand binding (e.g. Figitumumab)
* Well tolerated
* Promising results in (rare) Ewing sarcoma
* Phase II results discouraging in cancers of “corporate” interest (most common cancers)
* several trials stopped early because interim data provided no evidence of beneficial effect

31
Q

Anti-IGF-I therapy: why is it not as good as one would expect and how could this be fixed in future treatments?

A
  • Reduced negative feedback, therefore increased GH/IGF release?
  • Tumours have heterogeneous IGF1R expression?

Future:
* Need biomarker to identify appropriate people to treat
* IGF1R as an adjuvant or secondary target?
* target IR as well

32
Q

Improved stress resistance: by what mechanism may GH/IGF k/o result in this?

A

Ames dwarf mice:
* Mutation in Prop-1 (prevents differentiation of somatotrophs)
* males & females live 49% & 64% longer
* Given Diquat (50mg/kg) – potent inducer of oxidative stress - GH/IGF k/o’s tolerate it way better

33
Q

GH/IGF: how may they affect lifespan?

A

Reduction in GH / IGF-I signalling extends lifespan:
* Mutations & caloric restriction
* Analysis of human IGF1R gene: over-representation of heterozygous mutations associated with reduced receptor activity in centenarians (those over 100yrs olf)
* Some controversies but broadly supported in worms, flies mice & humans;
* Improved stress resistance
* Improved insulin sensitivity - decreased pancreatic mass, beta cell mass, insulin levels, and then insulin sensitivity
* Adipose function - increased adiposity and adiponectin - anti-inflammatory and insulin sensitivity effects
* Decreased tumor formation

34
Q

GH/IGF: how may they affect healthspan?

A

GH & IGF-I levels decrease with advancing age – somatopause:
* Correlates with increased fat / decreased muscle mass & physical fitness
* GH therapy as an anti-ageing regimen?
* Short-term trials in older men suggest favourable effects on lean muscle mass but little evidence of improved muscle strength/performance or quality of life
* Longer studies needed

35
Q

hGH: what is it and what does it do?

A

“hGH is the anti-ageing serum rejuvenating every cell in your body”

BIOL31571 (17 decks)

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