Puberty

Question 1

What is puberty?

Answer 1

• developmental event
• leading to somatic and sexual maturation
  -profound physiological, psychological and physical changes
• reproductive perspective: goal to produce mature gametes (spermatozoa and oocyte)
• breast development in females and increased testicular volume in males

Question 2

What is adrenarche characterised by?

Answer 2

• first endocrine process of puberty
• occurs around 6-8 y/o
  characterised by re- instigation of adrenal androgen secretion- DHEA (after 5yrs).
  -androgen secretion from zona retcularis
  -no change in cortisol

Question 3

What are two endocrine events of puberty?

Answer 3

1. Adrenarche->adrenal androgens
2. Gonadarche -> LH/FSH

Question 4

How does adrenal remodelling occur during development?

Answer 4

• fetus /neonate = DHEA produced
• infant - 5 y/o = no DHEA
  -6 y/o = functional ZR developed - DHEA and 12- 13 ZR expansion.

Question 5

histology of adrenal gland

Answer 5

outside -> inside
- zona glomerulosa (ZG)
-Zona fasciculata (ZF)
-Zona reticularis (ZR
-medulla (M)

Question 6

How is DHEA made?

Answer 6

• cholestrol is the main precursor
  -cholestrol -> pregnenolone -> 17 alpha hydroxypregnenolone -> DHEA -> DHEA - sulfate

Question 7

What is the function of DHEA?

Answer 7

adrenal -> circulation -> peripheral tissue (hair follicle, genital skin for pubic hair)

Question 8

Can ACTH instigate adrenarche?

Answer 8

• ACTH?
  -children with ACTH receptor mutation fail to undergo adrenarche so maybe ACTH is involved
  => but no change in ACTH/cortisol during adrenarche so maybe not

Question 9

What other factors instigate adrenarche?

Answer 9

1. POMC?
   - proximal 18 AA region that positively regulated adrenal androgen production.
   -in vitro studies did not substantiate this
2. POMC - related peptides?
   - b- lipotrophin and b-endotrophin plasma levels correlate with increase DHEA/S at adrenarche but no direct causal link
3. other factors ruled out include , IGF- 1 and insulin
   => no conclusive mechanism for control of adrenarch e

Question 10

What comes first?

Answer 10

Adrenarche before gonadarche

Question 11

What is gonadarche?

Answer 11

• reactivation of the HPG axis
• several years after adrenarche (typically ~11yrs)
• driven by hypothalamic GnRH and pituitary gonadotrophins
  -puberty depends on reactivation of GnRH release

Question 12

Why can we find out gender only on week 20 scan?

Answer 12

• HPG axis needs to be switched on to identify gender
• only switched on in week 16 and switched off just after birth then again switched on between 1-2

Question 13

GnRH and puberty

Answer 13

Neurones restrained during postnatal period until 10 years or more.
At puberty a gradual rise in pulsatile release - around 1 year before breast budding is observed.
GnRH levels high at night

Question 14

What is consonance?

Answer 14

• individual goes in order from stage 1 to 5 of the tanner stages of puberty.
• what varies is the duration a person stays at each stage

Question 15

What are the 5 stages of Tanner stages?

Answer 15

• 3 categories : breast development(girls), pubic hair development, genital development (boys)
• 1 : no breast, no pubic hair and prepupertal genital
  -2: breasts bud , few hairs, testis enlarged to 4mL
  -3: enlarged breast and areola , more pigmented hair , penis enlarges in length.
  -4: projection of areola above breast , small adult configuration, growth of penis in length and diameter
  -5: papilla projects out of areola, adult configuration with hair spread onto inner thighs, testis, scrotum and penis adult size.

Question 16

Why is timing of puberty(early) so important?

Answer 16

There are potential risks from early puberty :

-CVS disease
-metabolic disease
-obesity
- diabetes
-disordered behaviour
- decreased adult height
- decreased life expectancy

Question 17

What controls onset of puberty?

Answer 17

• dialogue between our individual genetics and environmental factors
• all have an effect at different points of the HPG axis
  Excess energy and fat causes earlier puberty = age of onset of puberty in USA and Uk is younger

Theory:
- inherent maturation of CNS
- body fat/nutrition - leptin/chrelin
-hypothalmic hormones - kisspeptin
- latest theory : epigenetics

Question 17

how has onset of puberty changed?

Answer 17

• menarche onset is at an earlier average age 12.5 y/o in UK - trend in europe and USA also similar
• link between energy and homeostasis and reproduction
• extremes of energy excess(body fat mass) impact the timing of puberty in both sexes- particularly females = better diets in Uk with high energy
• under and over nutrition in feotal/ neonates alters the timing of puberty in rodents and humans
• morbid obsesity can cause precocious puberty
• critical fat mass hypothesis : a threshold % of fat/body weight is required to attain(17%) and maintain female reproductive ability (22%)

Question 18

What animal studies show the link between body mass and fertility?

Answer 18

Leptin released from adiposetissue = fat tissue

1. 1950s ob/ob Leptin KO mouse
   - INFERTILE

Leptin directly excites kisspeptin in puberty
Pubertal mice in fed state = high leptin = high kisspeptin released = more GnRH and puberty
Pubertal mice starvation state = less leptin = low kisspeptin released = less GnRH and puberty

2. 1994 : leptin gene clones
   - ob/ob mice and humans - hypogonadotrophic , hypogonadism
   - delayed /absent puberty
   - can be reversed with leptin injection
   - some leptin deficient patients have normal menses /LH /estrodiol

Question 19

is leptin the trigger to puberty?

Answer 19

• obesity increases leptin levels and earlier puberty occurs
  -KO leptin in rodents and humans - delayed/absent puberty
• but leptin administration can not stimulate early puberty
• no leptin receptors on GnRH neurons to activate gonadarche
• threshold of leptin required to be reached for puberty but not a driver of puberty itself.

Question 20

How does ghrelin influence puberty?

Answer 20

• Gherlin sense fasted state, to stimulate feeding and fat deposition
• in starvation (high ghrelin) decreased activity of the HPG axis
  -Ghrelin decreases as puberty proceeds
• Ghrelin can decrease hypothalamic Kiss 1 expression in rat
• oestradiol can also increase GHSR expression and response to ghrelin in kiss1 neurons
  => low levels of leptin and high levels ghrelin -> decreased LH

Question 21

How does kisspeptin influence puberty?

Answer 21

Graph shows increased KISS-1 mRNA in pubertal monkey than in juvenile but about the same levels of GPR54 mRNA in both, so increased KISS1 levels is what drives puberty as the receptors remain the same

Question 21

What is the effect of continuous kisspeptin infusion in the release of LH in juvenile rhesus monkeys?

Answer 21

• initial spike then decrease until HPG axis shuts down, this is because initially there are a lot of free GPR54 for kisspeptin to bind to causing increased release of GnRH , more LH from the pituitary but once the GPR54 receptors get used up( the receptors levels are the same , only kisspeptin level increases in pubertal monkeys compared to juvenile) there is a decline in LH secretion downstream when continuous kisspetin infused.

Question 22

What is the effect of pulsatile kisspeptin administration on LH secretion in juvenile rhesus monkeys?

Answer 22

pulsatility is crucial for hormone function, so puberty can happen in correctly and development can happen in consonance, pulsitile release determines whether FSH or LH is secreted (FSH- slow , LH - fast)

Question 23

What does mutations in GPR54 (KP receptor) or the lack of kisspeptin cause?

Answer 23

- Kisspeptin is upstream to GnRH so abnormal development of GnRH neurones ->hypogonadism - failure to enter puberty -KO mice for GPR54 or kisspeptin ->hypothalmic hypogonadism - mutations in humans - > hypothalmic hypogonadism - activating mutations of GPR54 -> precocious puberty

Question 24

What is the effects of starvation on the expression of kisspeptin in the hypothalamus of pubertal and adult mice?

Answer 24

Decrease in leptin in starvation = decrease in kiss-1 = decrease in GnRH = decrease in LH and FSH = hypogonadism leptin directly exites kiss -1 neurones in ARC = leptin deficiency decreased kiss-1 mRNA in ARC but this is only in 10 -40% of people - only 10 - 40% of Kiss1 neurons express leptin receptors ++in other 60% decrease in leptin could be due to mutations in kiss-1 mRNA pubertal : fed = high expression of KP, starving = low expression of KP Adults : fed= high expression of KP, fasted = relatively high too of KP

Question 25

how does kisspeptin-GnRH system intergrate with metabolic cues?

Answer 25

- reduced leptin in starvation = decreased GnRH secretion - leptin directly excites kiss1 neurones in ARC - leptin deficiency = decreased kiss 1 mRNA in ARC - but only 10-40% of kiss 1 neurones express lepR.

Question 26

nutrition and body fat

Answer 26

extreme of energy excess (body fat) impacts the timing of puberty in both sexes -Rodent : under or over nutrition in foetal or neonates alters timing of onset of puberty -morbid obesity can cause precacious puberty - Fisch et al. "critical fact mass" hypothesis : threshold % of fat/body weight is required to attain (17%) and maintain ((22%) reproductive ability.

Question 27

Ob/Ob mice in the 1950s highlight the importance of leptin for reproductivity

Answer 27

Leptin-deficient mice get obese - leptin is a satiety hormone and regulates hunger, in mice with leptin deficiency no regulation led to them being obese but what was also seen in these mice was : infertility

Question 28

Influence of lack of leptin on the reproductive system

Answer 28

ob/ob mice and humans - hypogonadotropic hypogonadism -delayed/ absent puberty - can be reversed with leptin injections -some leptin-deficient patients have normal menses/LH/ Oestrodial levels though unknown why. => threshold of leptin is required to be reached for puberty but not the driver itself - permissive role on puberty onset

Question 29

Gut peptides : Ghrelin

Answer 29

Ghrelin senses the fasted state, to stimulate feeding and fat deposition so in starvation (high ghrelin) decreased activity of the HPG axis. - Ghrelin decreases as puberty proceeds -Ghrelin can decrease Kiss1 expression in rats (forbes et al 2009) -subset of kiss 1 neurones in selective hypothalamic nuclei express GHSR which responds to Ghrelin -oestradiol can also increase GHSR expression and respond to neurons (Frazao et al. 2014) -low levels of leptin and high levels of ghrelin => decreased puberty

Question 30

What are other theories for what controls puberty other than leptin and ghrelin?

Answer 30

-inheritant mutations in the GnRH or Kiss 1 neurone -epigenetics -mutation in GPR54 receptors or GnRH receptors - tumour in the pituitary /hypothalmus