Puberty Flashcards

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1
Q

What are the 2 endocrine events for puberty?

A

Adrenarche and gonadarche

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2
Q

What is adrenarche?

A
  • 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
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3
Q

What happens is gonadarche?

A

(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
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4
Q

What do adrenal androgens do?

A

They’re responsible for:

  • growth of pubic and axillary hair
  • growth in height
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5
Q

What do LH and FSH do in puberty?

A
  • 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
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6
Q

Where is the androgen (DHEA/DHEAS) secretion from?

A

The zona reticularis (the inner most layer of the adrenal cortex)

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7
Q

What happens in the zona reticularis that leads to the production and secretion of androgens?

A

Inherent maturation of cellular compartments of adrenal cortex – There is remodelling of the adrenal cortex that occurs

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8
Q

When do androgens surge and peak?

A

Surge from around ages 6-8, Peak at mid 20s and then a decline

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9
Q

Describe adrenal remodelling in detail

A
  • 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
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10
Q

List the sections of the adrenal cortex from outermost to inner most.

A
  • Zona glomerulosa
  • Zona fasciculata
  • Zona reticularis
  • Medulla (not part of the adrenal cortex but comes after ZR)
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11
Q

How is DHEA/S made

A

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
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12
Q

What enzyme makes DHEA?

A

CYP17,20 lyase

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13
Q

What enzyme makes DHEAS?

A

SULT2A1

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14
Q

What happens to the expression of CYP11A and CYP 17,20 lyase during puberty?

A

It increase in the zona reticularis

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15
Q

What does 3βHSD do?

A

It’s part of a side pathway and it converts cholesterol and pregnenolone into mineralocorticoids and glucocorticoids

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16
Q

What happens to 3βHSD expression ?

A

It reduces - during adrenarche the pathway shuts down so the pregnenolone and cholesterol makes more DHEA/DHEAS

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17
Q

What enzyme expression increases in the ZR during adrenarche?

A

SULT2A1, CYP11A and CYP 17,20 lyase

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18
Q

What is the function of DHEA and DHEAS?

A

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

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19
Q

What instigates adrenarche?

A

Not exactly sure but it could be:

  • ACTH
  • POMC (pro-opiomelanocortin)
  • POMC related peptides
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20
Q

Evidence that ACTH instigates adrenarche?

A
  • 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?
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21
Q

Evidence that POMC instigates adrenarche?

A
  • 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
22
Q

Evidence that POMC related peptides instigate adrenarche?

A

b-lipotrophin and b-endorphin plasma levels correlate with increased DHEA/S at adrenarche

23
Q

What does puberty depend on?

A

The reactivation of the HPG axis/GnRH release

24
Q

What does the reactivation of the HPG axis do?

A

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

25
Q

When is the HPG axis turned on and off?

A

• 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
26
Q

When do GnRH levels usually increase?

A

GnRH levels increase at night, as you go through puberty it becomes more consistent

27
Q

What controls the onset of puberty?

A
  • Both our individual genetics and environmental factors

- Link between energy homeostasis & reproduction

28
Q

What can cause potential adverse risks from early puberty?

A
  • cardiovascular disease
  • metabolic disease
  • obesity
  • diabetes
  • disordered behaviour
  • decreased adult height
  • decreased life expectancy
29
Q

What are the 4 theories about what causes the onset of puberty?

A
  • Inherent maturation of CNS
  • Body fat/nutrition – Leptin and Ghrelin?
  • Hypothalamic hormones - Kisspeptin, other factors
  • Latest theories - Epigenetics?
30
Q

How does nutrition and body fat affect puberty?

A
  • 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
31
Q

How do the gut and adipose tissue affect the gonadal function?

A

Secretions from the gut and adipose tissue act on the hypothalamus and modulate the gonadal function via the HPG axis

32
Q

How do leptin mutations affect adipose tissue and fertility?

A
  • 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
33
Q

What is leptin?

A
  • 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
34
Q

Evidence that leptin may trigger puberty

A

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.
35
Q

What is ghrelin?

A
  • 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
36
Q

What does a bolus of ghrelin stimulate?

A

The GH-IGF axis (growth hormone-insulin like growth factor) via the ghrelin receptor (GHSR)

37
Q

What happens to ghrelin as puberty proceeds?

A

Ghrelin decreases

38
Q

How does ghrelin affect the hypothalamic kiss1 expression?

A
  • 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.
39
Q

How does oestradiol affect GHSR?

A

Oestradiol can also increase GHSR expression and response to Ghrelin in kiss1 neurons.

40
Q

How do leptin and ghrelin affect LH?

A

Low levels of leptin and high levels of ghrelin decrease LH

41
Q

What is kisspeptin?

A

A hypothalamic hormone

42
Q

Where are kisspeptin receptors expressed?

A

On the GnRH neurones of the arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV) of the hypothalamus

43
Q

What evidence is there that kisspeptin may trigger puberty?

A

In pubertal monkeys there was an increase in Kiss mRna but the receptor levels were the same

44
Q

How does continuous kisspeptin affect LH?

A

Continuous GnRH and kisspeptin cause LH levels to drop

45
Q

How do pulses of kisspeptin affect LH?

A

Pulses of kisspeptin = pulses of LH

46
Q

What happens if there is no kisspeptin receptors/mutated kisspeptin receptors?

A
  • Abnormal development of GnRH neurones&raquo_space; hypogonadism
  • Failure to enter puberty
  • KO mice for GPR54 or kisspeptin -> hypothalamic hypogonadism
  • Mutations in humans&raquo_space; hypothalamic hypogonadism
  • Activating mutations of GPR54 -> precocious puberty
47
Q

What is another name for kisspeptin receptors?

A

GPR54

48
Q

What is the phenotype seen in mice with null kisspeptin receptors?

A

Male: small testes and epididymis, delayed spermatogenesis infertility;

Female: small oviducts, folliculogenesis-no progression to ovulation, no oestrous cycles, infertility

49
Q

What drives kisspeptin?

A
  • If you are fed there’s a higher expression of kisspeptin

- Fasted state: decreased expression of kisspeptin, especially during puberty

50
Q

How do kisspeptin and GnRH intergrate with metabolic cues?

A
  • Reduced leptin in starvation, decreased GnRH secretion
  • Leptin directly excites Kiss1 neurones in ARC
  • Leptin deficiency&raquo_space;↓Kiss 1 mRNA in ARC&raquo_space; reduced GnRH and thus reduced LH/FSH&raquo_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