Lecture 14 - Pathophysiology of GH/IGF axis in postnatal life II Flashcards
GH/IGF abnormalities: how may they affect puberty and what treatments exist?
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
GH/IGF abnormalities: what may they be caused by?
- Genetic factors
- Epigenetic factors?
- Nutritional status
- Adiposity?
Gonaodotrophs: what axis are they involved in and what do each stage do?
Hypothalamus - Gonadotrophin Releasing Hormone (GnRH)
Anterior pituitary - Gonadotrophs
Gonads - affects gametes/sex steroids
Puberty: by what mechanism is it initiated?
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
KNDy neuron: what is it, what does it do, and what is it activated and inhibited by?
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)
Menstrual cycle: what two parts of it are there?
- Uterine cycle
- Ovarian cycle
Uterine cycle
- Menstrual phase - ~5 days
- Proliferative phase - ~9 days
- Secretory phase - ~14 days
Ovarian cycle
- Follicular phase - ~14 days
- Luteal phase - ~14 days
Dominant follicle: how is it produced?
One of the tertiary follicles will become the dominant follicle
IGF-1 required
IGF: what is it, what is its role in follicle development and ovulation, and how is it regulated?
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
Follicular development: what causes it to occur, and what are the stages?
Gonadotrophin-dependent initially
- Primordial follicles
- Primary follicles
- Secondary follicles
- Tertiary follicles
Primordial follicles: what are they, what stage of meiosis development are the oocytes in, and what are their granulosa cells like?
Structure containing an immature oocyte and a layer of granulosa cells
1st meiotic prophase
Single-layer, flat
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?
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
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?
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
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?
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
Granulosa cells: what are they and what do they do?
Cells in the ovarian follicles that support oocyte development
Theca cells: what are they and what do they do?
Endocrine cells in the interfollicular stroma that affect reproduction and fertility
IGF-I production: what gonadotroph may it be stimulated by and by what mechanism may this occur?
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
IGFBPs: what are they, what do they do, and what are they inhibited by?
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
How do stromal and epithelial cells communicate?
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
IGF-I receptor inhibition: what causes it and what does it cause to happen?
PPP
Prevents estrogen-induced proliferation
E: what is it, what does it do, and what is it inhibited by?
Estrogen
Stimulates IGF-1 expression in stroma
Inhibition of the IGF-1 receptor
PPP: what is it and what does it do?
Picropodophyllin - an IGF-I receptor inhibitor
- PPP (in uterine lumen) blocks E-mediated activation of IGF-1 receptor
- PPP inhibits E-stimulated epithelial proliferation
IGF/IGF1R and cancer: what is their relationship?
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
IGF/IGF1R and cancer: what evidence is there to support their relationship?
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
Acromegaly: since IGF-I overexpression causes an increased cancer risk, does this also occur in those with acromegaly?
Acromegaly is not associated with an increased risk of prostate/breast cancer
IGF-I: what is the treatment of those with high levels?
Licenced & unlicensed use of GH & IGF-I
Treatment with IGF-1: what are the potential issues?
No cases of malignancy reported to date but current data from a small population and short time frame so more follow-up needed
GH usage: what studies have occurred to investigate the potential relationship with cancer and what was found?
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
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?
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
Anti-IGF-I therapy: why is it not as good as one would expect and how could this be fixed in future treatments?
- 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
Improved stress resistance: by what mechanism may GH/IGF k/o result in this?
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
GH/IGF: how may they affect lifespan?
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
GH/IGF: how may they affect healthspan?
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
hGH: what is it and what does it do?
“hGH is the anti-ageing serum rejuvenating every cell in your body”
