Puberty Flashcards
What are the 2 endocrine events for puberty?
Adrenarche and gonadarche
What is adrenarche?
- First endocrine process of puberty
- Occurs ~6-8 years
- Characterised by (re-)instigation of adrenal androgen secretion:
o Dehydro-epiandrosterone (DHEA)
o Dehydro-epiandrosterone sulphate (DHEA-S)
o No change in cortisol/other adrenal hormones - not a global activation of HPA axis
What happens is gonadarche?
(Re-)Activation of HPG axis:
• Several years after adrenarche (typically ~11 yrs of age).
- Driven by hypothalamic GnRH & pituitary gonadotrophins
- The initiation of production of LH and FSH
What do adrenal androgens do?
They’re responsible for:
- growth of pubic and axillary hair
- growth in height
What do LH and FSH do in puberty?
- LH: leads to steroid synthesis which leads to development of secondary sex characteristics
- FSH: leads to steroid synthesis/ the growth of testis in men/ folliculogenesis in women
Where is the androgen (DHEA/DHEAS) secretion from?
The zona reticularis (the inner most layer of the adrenal cortex)
What happens in the zona reticularis that leads to the production and secretion of androgens?
Inherent maturation of cellular compartments of adrenal cortex – There is remodelling of the adrenal cortex that occurs
When do androgens surge and peak?
Surge from around ages 6-8, Peak at mid 20s and then a decline
Describe adrenal remodelling in detail
- It begins in the foetal phase – adrenal gland has 2 zones: foetal zone and the definitive zone. Foetal zone is responsible for DHEA and DHEAS production in the foetus
- After the foetus is born there is a shrinkage of the foetal zone and this is accompanied by a drop in the DHEA/DHEAS production
- After that the definitive zone expands and differentiates into layers of the adrenal cortex (zona glomerulosa and zona fasciculata) – at this point DHEA and DHEAS production is off
- Focal islands of the zona reticularis form and expand.
- Zona reticularis develops – DHEA/DHEAS production is switched back on and the remodelling is complete. ZR is the one producing the androgens
- Up until puberty ZR expands
List the sections of the adrenal cortex from outermost to inner most.
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
- Medulla (not part of the adrenal cortex but comes after ZR)
How is DHEA/S made
Via steroidogenic conversions with the aid of steroidogenic enzymes:
- Cholesterol to pregnenolone to hydroxyprenenolone to DHEA
- CYP11A – converts progesterone into pregnenolone
- CYP17,20 lyase is responsible for DHEA production
- SULT2A1 – responsible for DHEA-sulfate
What enzyme makes DHEA?
CYP17,20 lyase
What enzyme makes DHEAS?
SULT2A1
What happens to the expression of CYP11A and CYP 17,20 lyase during puberty?
It increase in the zona reticularis
What does 3βHSD do?
It’s part of a side pathway and it converts cholesterol and pregnenolone into mineralocorticoids and glucocorticoids
What happens to 3βHSD expression ?
It reduces - during adrenarche the pathway shuts down so the pregnenolone and cholesterol makes more DHEA/DHEAS
What enzyme expression increases in the ZR during adrenarche?
SULT2A1, CYP11A and CYP 17,20 lyase
What is the function of DHEA and DHEAS?
It’s converted into DHT in the peripheral tissue – DHT is responsible for pubic hair, axillary hair, for the change in the skin gland and prostate secretions
What instigates adrenarche?
Not exactly sure but it could be:
- ACTH
- POMC (pro-opiomelanocortin)
- POMC related peptides
Evidence that ACTH instigates adrenarche?
- Dexamethasone (synthetic corticosteroid) suppresses adrenal androgen production
- Children with ACTH receptor mutations fail to undergo adrenarche.
- But no change in ACTH/cortisol during adrenarche
- Divergent mechanisms for cortisol and androgen production at adrenarche?
Evidence that POMC instigates adrenarche?
- 241AA sequence that undergoes cleavage into multiple peptides.
- Proximal 18 AA region that positively regulated adrenal androgen production.
- In vitro studies did not substantiate this
Evidence that POMC related peptides instigate adrenarche?
b-lipotrophin and b-endorphin plasma levels correlate with increased DHEA/S at adrenarche
What does puberty depend on?
The reactivation of the HPG axis/GnRH release
What does the reactivation of the HPG axis do?
GnRH is synthesised & secreted
↓
Synthesis and secretion of pituitary gonadotrophins (LH & FSH)
↓
Gonadal steroid production
↓
Negatively/positively feedback onto hypothalamus-pituitary to regulate GnRH and LH/FSH production
When is the HPG axis turned on and off?
• 16th gestational week - activation of HPG axis for the first time (needed for completion of sexual differentiation)
o Pulsatile GnRH secretion in foetus, switched off and turned on again 1-2 years postnatal (almost like priming of the HPG axis).
- Neurones ‘restrained’ during postnatal period - 10 years or more
- At puberty a gradual rise in pulsatile release - around 1 year before breast budding observed
When do GnRH levels usually increase?
GnRH levels increase at night, as you go through puberty it becomes more consistent
What controls the onset of puberty?
- Both our individual genetics and environmental factors
- Link between energy homeostasis & reproduction
What can cause potential adverse risks from early puberty?
- cardiovascular disease
- metabolic disease
- obesity
- diabetes
- disordered behaviour
- decreased adult height
- decreased life expectancy
What are the 4 theories about what causes the onset of puberty?
- Inherent maturation of CNS
- Body fat/nutrition – Leptin and Ghrelin?
- Hypothalamic hormones - Kisspeptin, other factors
- Latest theories - Epigenetics?
How does nutrition and body fat affect puberty?
- Extremes of energy excess (body fat mass) impact the timing of puberty in both sexes - particularly females
- Under- and over-nutrition in foetal and/or neonates alters the timing of puberty in rodents and humans
- Morbid obesity (females) can cause precocious puberty
- Pregnancy and lactation require a lot of energy – cant be pregnant if you’re underweight/lack energy
How do the gut and adipose tissue affect the gonadal function?
Secretions from the gut and adipose tissue act on the hypothalamus and modulate the gonadal function via the HPG axis
How do leptin mutations affect adipose tissue and fertility?
- Leptin deficient: In extreme cases of obesity there is a spontaneous mutation in the leptin coding gene, not enough leptin made
Mice that are leptin deficient tend to be:
- Hyperphagic
- Hyperglycaemic
- Insulin resistant
- Infertile
- Delayed or absent puberty
What is leptin?
- Hormone expressed in adipocytes
- Signals satiety to the brain
- Stimulates energy expenditure
- Circulating levels directly proportional to the amount of body fat
- In less extreme cases of obesity, it believed leptin exists but the receptor is faulty
- In extreme cases, the leptin gene is faulty and leptin does not exist in the body- influence on reproductive system
Evidence that leptin may trigger puberty
Sexual dimorphism:
- Females- leptin rise ~ 2 years prior to puberty (increased GnRH pulsatility)
- Males - no rise
- Obesity increases leptin and earlier puberty occurs
- Knock-out leptin in rodents and humans- delayed/absent puberty
- BUT, leptin administration can not stimulate early puberty
- No leptin receptors on GnRH neurons
- Threshold of leptin required to be reached for puberty but not a driver of puberty itself.
What is ghrelin?
- A gut hormone
- Senses a fasted state, tells the body to eat
- During fasted state there’s a high ghrelin and decreased activity of the HPG axis
What does a bolus of ghrelin stimulate?
The GH-IGF axis (growth hormone-insulin like growth factor) via the ghrelin receptor (GHSR)
What happens to ghrelin as puberty proceeds?
Ghrelin decreases
How does ghrelin affect the hypothalamic kiss1 expression?
- Ghrelin can decrease hypothalamic kiss1 expression in rats.
- There’s a subset of kiss1 neurons in selective hypothalamic nuclei that express GHSR and respond to Ghrelin.
How does oestradiol affect GHSR?
Oestradiol can also increase GHSR expression and response to Ghrelin in kiss1 neurons.
How do leptin and ghrelin affect LH?
Low levels of leptin and high levels of ghrelin decrease LH
What is kisspeptin?
A hypothalamic hormone
Where are kisspeptin receptors expressed?
On the GnRH neurones of the arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV) of the hypothalamus
What evidence is there that kisspeptin may trigger puberty?
In pubertal monkeys there was an increase in Kiss mRna but the receptor levels were the same
How does continuous kisspeptin affect LH?
Continuous GnRH and kisspeptin cause LH levels to drop
How do pulses of kisspeptin affect LH?
Pulses of kisspeptin = pulses of LH
What happens if there is no kisspeptin receptors/mutated kisspeptin receptors?
- Abnormal development of GnRH neurones»_space; hypogonadism
- Failure to enter puberty
- KO mice for GPR54 or kisspeptin -> hypothalamic hypogonadism
- Mutations in humans»_space; hypothalamic hypogonadism
- Activating mutations of GPR54 -> precocious puberty
What is another name for kisspeptin receptors?
GPR54
What is the phenotype seen in mice with null kisspeptin receptors?
Male: small testes and epididymis, delayed spermatogenesis infertility;
Female: small oviducts, folliculogenesis-no progression to ovulation, no oestrous cycles, infertility
What drives kisspeptin?
- If you are fed there’s a higher expression of kisspeptin
- Fasted state: decreased expression of kisspeptin, especially during puberty
How do kisspeptin and GnRH intergrate with metabolic cues?
- Reduced leptin in starvation, decreased GnRH secretion
- Leptin directly excites Kiss1 neurones in ARC
- Leptin deficiency»_space;↓Kiss 1 mRNA in ARC»_space; reduced GnRH and thus reduced LH/FSH»_space; reduced activity of the gonads
- But only 10-40% of Kiss1 neurones express LepR
- Indirect and direct mechanisms of Leptin action in hypothalamus on HPG axis
