Puberty Flashcards

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1
Q

Summarise Puberty (5)

A
  • Complex developmental event
  • Continuum of changes leading to somatic and sexual maturation
  • Profound physiological, psychological and physical changes
  • Reproductive perspective: goal to produce mature gametes:
  • Testes -> spermatozoa
  • Ovaries -> oocyte
  • Breast development in females, and increased testicular volume in males
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2
Q

What is the clinical sign of puberty (male and female) (2)

A

male: increase in testicular vol.
female: breast development

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3
Q

2 endocrine events of puberty (2)

A

1) adrenarche: stim. of adrenal androgens = growth of pubic + axillary hair, height

2) Gonadarche: activat. of HPG Axis (LH +FSH) =>
LH= steroid synth: secondary sex characteristics
FSH= growth of testis/folliculogenesis/steroid synth

together = puberty

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4
Q

Adrenarche (3)

A
  • First endocrine process of puberty : ~6-8 years
  • Characterised by (re-)instigation of adrenal androgen secretion
    -Dehydro-epiandrosterone (DHEA)
    -Dehydro-epiandrosterone sulphate (DHEA-S)
  • No chance cortisol/other adrenal hormones - not a global activation of axis
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5
Q

DHEA/DHEAS pattern in life (7)

A

1)high @ birth
2) drops down (0)
3) rises at puberty (6-8)
4) rises + peaks at 20@s
5) gradual decline

  • Androgen secretion is from the zona reticularis

-Result of inherent maturation of cellular compartments of adrenal cortex

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6
Q

Adrenal remodelling during development - 2 enzymes

A

Most of ZR dev. during puberty vis adrenal remodelling
image

expression of SULT2A1 and shutdown of 3betaHSD

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7
Q

How is DHEA/S made? (5)

A

Image

1) Cholesterol
2) Pregnenolone
3) 17-alpha-Hydroxypregeneolone (using CYP17)
4)DHEA (using CYP17)
5)DHEA Sulfate (using SULT2A1)

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8
Q

Where is the downregulation during the creation of DHEA/S? (

A

side pathway/shunting of pregnenolone shut down during adrenarche to allow for all cholesterol to be committed to DHEA/S production = downregulated 3betaHSD expression

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9
Q

Functions of DHEA/S (4)

A

Image

1) adrenal tissue: created as cholesterol products
2) into circulation (blood)
3) peripheral tissue (e.g. prostate, hair follicle, genital skin): (as other products): converted into DHT and 5,11OHT via metabolism
4) hence pubic hair, axillary hair etc.

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10
Q

What instigates adrenarche? ACTH evidence (4)

A

But no change in ACTH/cortisol during adrenarche = NOT A CANDIDATE XXXXXXX

1) Dexamethasone (synth. steroid) suppressed adrenal androgen production
2) Children with ACTH receptor mutation fail to undergo adrenarche

Divergent mechanisms for cortisol and androgen production at
adrenarche? (not conclusive)

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11
Q

What instigates adrenarche? POMC evidence

A

Peptide: Proximal 18 AA region that positively regulated adrenal androgen production.

However:
* In vitro studies did not substantiate this (not conclusive)

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12
Q

What instigates adrenarche? POMC related peptides

A

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

but no direct linkage established (not conclusive)

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13
Q

What instigates adrenarche? Other factors ruled out

A

Include Prolactin, IGF-1 and insulin were ruled out
= no conclusive mechanism for control of adrenarche

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14
Q

Gonadarche (4)

A
  • (Re-)Activation of HPG axis.
  • Several years after adrenarche (typically ~11 yrs of age).
  • Driven by hypothalamic GnRH & pituitary gonadotrophins.
    HPG: GnRh -> LH/FSH -> steroidogenesis
    = puberty depends on the reactivation of GnRH release
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15
Q

HPG axis and Puberty on/off (8)

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)

1) 16th gestational week activation of HPG axis. (sex confirmation @ 20wk scan)

2) just before birth = switched off

3) After birth: Pulsatile GnRH secretion switched on in foetus and 1-2 years postnatal increased.

4) After this: switched off - Neurones ‘restrained’ during postnatal period -> 10 years or more

5) At puberty: re-activated = a gradual rise in pulsatile release- around 1 year before breast budding observed

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16
Q

Consonance and Tanner stages of puberty (5)

A

everyone goes through each stages - only things that vary: time spent in each stage + time taken to move from one stage to another = consonance -> useful for diagnosing sex disorder

Stage 1: no dev. breast and testis
Stage 2:
Stage 3:
Stage 4:
Stage 5: full dev.

17
Q

Consonant growth and sexual development milestones (4)

A

Pubic hair: 2-3-4-5 (13-16 b), (11-13,13-15 g)
Testes/ Breast: 2-3-4-5 (12-15 b), (11-13,13-15 g)
Penis/Menarche: 2-3-4-5 (girls=13yrs)
Growth: 12-16yrs(b), 11-15yrs(g)

18
Q

Why the fuss about the timing of puberty? (5)

A

Potential adverse risks from early puberty:
- cardiovascular disease
- metabolic disease
- obesity
- diabetes
- disordered behaviour - sexual maturity before psychological
- decreased adult height - bone fusion earlier
- decreased life expectancy

19
Q

What controls the onset of puberty? (7)

A
  • Dialogue between our individual genetics + environmental factors
  • All impinge at different points of the HPG axis

A number of theories have been put forward:
– Inherent maturation of CNS
– Body fat/nutrition – Leptin and Ghrelin?
– Hypothalamic hormones -Kisspeptin, other factors?
– Latest theories - Epigenetics?

20
Q

Onset of puberty/menarche trends (2)

A

-Secular trend to earlier age at menarche in girls from W. Europe & USA » Average age of menarche onset in UK = 12.5yrs

-link b/w energy homeostasis + reproduction

image

21
Q

Nutrition and body fat(5)

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
  • Frisch et al.: “critical fat mass” hypothesis
    -Threshold % fat/body weight is required to attain (17%) and maintain female reproductive ability (22%) -> energy intensive stages = need enough energy to undergo

Cross talk between metabolic status and puberty onset/maintenance of reproduction

22
Q

Nutritional gating and puberty-gut,adipose,hypo (3)

A

evidence to show hypothalamus: gut, adipose tissue, gonadal function

communication b/w gut secretions + adipose tissue secretions act on hypo = modulates axis (gonadal function)

23
Q

Adipose Tissue: Leptin (Mice) (5)

A

1950’s: ob/ob mouse
* Hyperphagic
* Hyperglycaemic
* Insulin resistant
* Infertile
* Leptin deficient

24
Q

Adipose Tissue: Leptin (kid) (7)

A
  • 1994: leptin gene cloned
  • Expressed in adipocytes-WAT
  • Sensor of energy sufficiency
  • Satiety factor - tells brain you’re full
  • Stimulates energy expenditure
  • Circulating levels directly proportional to amount of body fat
  • Influence on reproductive system
    -ob/ob mice & humans - hypogonadotrophic hypogonadism
    -Delayed/absent puberty
    -Can be reversed with leptin injection
    -Some leptin-deficient patients have normal menses/LH/oestradial levels- unknown why.
25
Q

Is leptin the trigger to puberty? (6)

A
  • Sexual dimorphism:
  • Females- rise ~ 2 years prior to puberty (increased GnRH pulsatility)
  • Males- no rise
  • Obesity increases leptin and earlier puberty occurs
  • KO leptin in rodents and humans- delayed/absent puberty
  • BUT, leptin administration cannot 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.

Leptin has a permissive role on puberty onset, not the ‘driver’

26
Q

Gut peptides: Ghrelin (8)

A
  • Ghrelin senses the fasted state, to stimulate feeding and fat deposition.
  • A bolus of ghrelin stimulates the GH/IGF axis Via GHSR.
  • In ‘starvation’ (high ghrelin) decreased activity of the HPG axis.
  • Ghrelin decreases as puberty proceeds.
  • Ghrelin can decrease hypothalamic kiss1 expression in rat (Forbes et al., 2009).
  • Subset of kiss1 neurons in selective hypothalamic nuclei that express GHSR and respond to Ghrelin.
  • Oestradiol can also increase GHSR expression and response to Ghrelin in kiss1 neurons (Frazao et al., 2014).
  • Low levels of leptin and high levels ghrelin = decreased LH
27
Q

KIsspeptin coexpression study (4)

A
  • Co-expression of GnRH mRNA with Kiss1R mRNA in rats from the medial preoptic area.
  • GnRH-mRNA-expressing cells =red.
  • Clusters of silver grains (white dots) =Kiss1R mRNA.
  • ¾ of the GnRH neurons co-express Kiss1R mRNA .
28
Q

Effect of continuous kisspeptin infusion on LH release in juvenile rhesus monkeys (3)

A

1)initial spike
2) gradual decline
3) complete shutdown

29
Q

Effect of pulsatile kisspeptin administration on LH secretion in juvenile rhesus monkeys

A

pulsatile GnRH and Kisspeptin
= pulsatility is crucial w/ respect to function

30
Q

Kisspeptin: a new role? (7)

A

Original observations in GPR54 null mice / humans (mutations):
-Abnormal development of GnRH neurones = hypogonadism
-Failure to enter puberty
-KO mice for GPR54 or kisspeptin = hypothalamic hypogonadism
-Mutations in humans- hypothalamic hypogonadism
-Activating mutations of GPR54 =precocious puberty

-Phenotype (mice) –
»Male: small testes and epididymis, delayed spermatogenesis infertility;
»Female: small oviducts, folliculogenesis-no progression to ovulation, no oestrous cycles, infertility

31
Q

GnRH neurones driven by kisspeptin at the onset of puberty?
What drives Kisspeptin?

Effects of starvation on the expression of Kisspeptin in the hypothalamus of pubertal and adult mice results (3)

A

puberty: low kisspeptin when fasted
adult: low diff
= direct link/effecr

32
Q

Integration of Kisspeptin-GnRH system with metabolic cues? (4)

A
  • Reduced leptin in starvation, decreased GnRH secretion
  • Leptin directly excites Kiss1 neurones in ARC
  • Leptin deficiency »↓Kiss 1 mRNA in ARC
  • But only 10-40% of Kiss1 neurones express LepR
    Indirect and direct mechanisms of Leptin action in hypothalamus on HPG axis
33
Q

New proposed mechanisms of interplay between energy homeostasis and HPG
axis

A

image