Puberty Flashcards
(24 cards)
What is Puberty?
Puberty is a complex developmental event that involves a continuum of changes leading to somatic and sexual maturation.
The changes which occur are psychological, physiological, and physical.
Puberty takes about 3-4 years to occur
In males, it results in the production of sperm and increased testicular volume.
In females, it results in the development of meiotically competent oocytes and breast development.
What are the two events in puberty?
There are two endocrine events in puberty.
Adrenarche is the switching on of adrenal androgens. This is responsible for pubic hair, axillary hair and growth in height.
Gonadarche is the switching on of the HPG axis, which results in steroid synthesis in the gonads, secondary sex characteristics, growth of gonads in males, and folliculogenesis in females.
These events are independently regulated.
What is Adrenarche?
Adrenarche is the first endocrine event in puberty which occurs at 6-8 years.
It is characterised by the re-instigation of the adrenal androgens; dehydro-epiandrosterone (DHEA) and dehydro-epiandrosterone sulphate (DHEAS) from the zona reticularis.
This is caused by the inherent maturation of the cellular compartments of the adrenal cortex. The secretion is caused by the remodelling of the adrenal cortex.
The levels of DHEA/S surge at around 6-8 years, peak at mid 20s, and then decline.
*Re-instigation: During foetal development, there are high levels of DHEA/S which dramatically decline after birth. When adrenarche begins, the levels of DHEA/S begin to rise.
Describe adrenal remodelling during development.
Adrenal remodelling results in the maturation of the cellular compartments of the adrenal cortex.
In the foetus, the adrenal cortex has two zones; the foetal zone and the definitive zone.
The foetal zone is responsible for producing DHEA/S. When the foetus develops and is born, there is an involution of the foetal zone, resulting in a decline in DHEA/S production.
The definitive zone expands into the layers of the adrenal cortex.
As an infant, the zora glomerulosa and zona fasciculata become developed.
At about 3 years, the zona reticularis begins to form from focal islands.
At about 4-5 years, the ZR focal islands begin to expand.
By about 6 years, adrenal remodelling is complete. The ZR is developed and is functional, and DHEA/S production begins again, allowing adrenarche to begin.
At around 12-13 years, the zona reticularis continues to expand causing a rise in DHEA/S production.
How is DHEA/S made?
DHEA is made in the zona reticularis in the adrenal cortex from the common precursor cholesterol. It undergoes a series of steroidogenic conversions aided by steroidgenic enzymes.
CY11A is responsible for converting cholesterol in to pregnenolone.
This is then converted by CY17 17alpha-hydroxylase to 17alpha-hydroxypregnenolone.
CYP17 17,20 lyase then converts this into DHEA.
SULT2A1 is then responsible for turning DHEA to DHEAS.
In an individual undergoing puberty, there is increased expression of CYP11A, CYP17, and SULT2A1 compared to a pre-pubertal individual.
3betaHSD modulates the conversion of cholesterol into mineralocorticoids and glucocorticoids. During adrenarche, the expression of 3BHSD is significantly reduced and downregulated. This is so cholesterol is committed towards making DHEA/S in the zona reticularis.
What is the function of DHEA/S?
Once synthesised by the ZR in the adrenal cortex. DHEA/S travels in the blood circulation and is metabolised by peripheral tissues where it is converted into DHT.
DHT is responsible for the growth of pubic hair, axillary hair, changes in skin gland and prostrate secretions.
What instigates adrenarche?
There is no conclusive mechanism for the control of adrenarche.
Some mechanisms that have been considered are:
ACTH: adrenocorticotropic hormone
This is because when dexamethasone, a synthetic corticosteroid, was administered, it resulted in the supression of the adrenal androgen production.
In addition to this, children with mutations in the ACTH receptor failed to undergo adrenarche.
HOWEVER, during adrenarche there is no change in the levels of ACTH and cortisol.
This suggests there is likely other mechanisms in play when it comes to the involvement of corticosteroids and androgen production during adrenarche.
POMC: pro-opiomelanocortin is a 241AA sequence which is cleaved into multiple peptides. The proximal 18 AA region positively regulated adrenal androgen production. This was shown by in vivo studies.
HOWEVER, in vitro studies did not substantiate this.
POMC-related peptides: b-lipotrophin and b-endorphin
correlated with increased DHEA/S at adrenarche.
However, there is no sufficient evidence to support this,
Other factors that have been ruled out are prolactin, insulin growth factor (IGF-1), and insulin.
What is Gonadarche
Gonadarche is the second endocrine event in puberty. This is the reactivation of the HPGaxis, which results in steroid synthesis in the gonads, secondary sex characteristics, growth of gonads in males, and folliculogenesis in females.
This occurs several years after adrenarche, at around 11 years of age.
GnRH is synthesised and secreted. This interacts with the anterior pituitary, resulting in the synthesis and secretion of gonadotrophins; LH and FSH which result in steroid production in the gonads.
In females: oestrogen is produced by the ovaries, causing the widening of hips, breast development, pubic and axillary hair and menstruation.
In males: testosterone is produced by the testes, causing breaks in the voice, growth of muscle tissue, enlargement of genitalia, and facial, pubic and axillary hair.
Describe GnRH during pre-puberty and puberty.
During the 16th gestational week, there is the activation of the HPGaxis and pulsatile GnRH is secreted. This is switched off just before birth.
After birth, the HPG axis is switched on again for 1 to 2 years postnatally and then is switched off again.
The GnRH neurones are then restrained during the postnatal period for roughly 10 years.
At puberty, there is a gradual rise in pulsatile GnRH.
This occurs 1 year before breast budding is observed in females.
Reactivation of the HPGaxis usually begins with nocturnal rises in GnRH levels. During puberty, the levels become more consistent throughout the day and there is an increased level of pulsatile GnRH. At the adult stage, you have a sustained pulsatile GnRH secretion. In women, there are cyclical differences.
What is the week you can determine the sex of a baby in an ultrasound scan?
week 20.
Define Consonance
Consonance is the smooth progression of physical changes occurring through puberty.
The length of time each stage takes does not matter, but the order of the stages is critical.
Takes about 3-4 years from instigation to completion.
What are the tanner stages of puberty in females.
stage 2: breast “buds” start to form; pubic hair starts to form
from stage 2 to 5, the breasts and pubic hair continue to develop. growth occurs between stages 2-5.
around stage 4, menarche (menstruation) begins, however, fertility does not occur until a year later.
What are the tanner stages of puberty in males.
testes and scrotum begin to enlarge and develop, pubic hair forms and develops. voice cracks and deepens. growth occurs.
sperm production starts at tanner stage 2. fertility begins once puberty begins.
Why is the timing of puberty important?
Early puberty can cause potential adverse risks such as
cardiovascular disease metabolic disease obesity diabetes disordered behaviour decreased adult height decreased life expectancy
What switches on puberty?
Puberty is switched on by an integration of central and peripheral inputs determined both by genetics and environmental factors, particularly nutrition
What are some of the inputs that have been hypothesised to switch on puberty?
o Inherent maturation of CNS
o body fat/nutrition – hormones: leptin & ghrelin
o hypothalamic hormones – kisspeptin
o Latest theories – epigenetics (study of how your behaviours + environment can cause changes in the way your genes work – changes in the expression of a gene, changes in the phenotype BUT without in sequence structure – these changes in expression can be passed down to offspring )
How is nutrition & body fat linked to puberty?
- Extremes of energy excess (body fat mass) impact the timing of puberty in both sexes – particularly females
- Morbid obesity (females) can cause precocious puberty
• Frisch et al: “critical fat mass” hypothesis
o there is a threshold %fat/body weight requires to attain (17%) and maintain female reproductive ability (22%)
o This is because pregnancy + lactation are energy intensive processes, so you need a certain amount of energy reserves
o The precursor of all steroid hormones is cholesterol – body fat
What is the link between nutritional gating and puberty
• Secretion from the gut + secretion on the adipose tissue act on the hypothalamus + in turn modulate gonadal function via HPG axis
Ghrelin is a gut peptide that is secreted.
Leptin is secreted from the adipose tissue.
Describe leptin
- Hormone expressed in adipocytes – white adipose tissue
- 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
o ob/ob mice & humans with leptin deficiency – hypogonadotrophic hypogonadism
o Delayed/absent puberty
o Can be reversed with leptin injection
o Some leptin-deficient patients have normal menses/LH/oestradial levels- unknown why.
Is leptin the trigger to puberty?
o Females – rise in leptin levels ~ 2 years prior to puberty (coincides with increased GnRH pulsatility)
o Males – no rise in leptin levels
• Obesity increases leptin and earlier puberty occurs
• Knockout leptin in rodents and humans – delayed/absent puberty
• BUT leptin administration cannot stimulate early puberty
• no leptin receptors on GnRH neurons, no direct regulation of GnRH via leptin
• however, there is a threshold of leptin required to be reached for puberty but not a driver of puberty itself
Leptin has a permissive role on puberty onset but it is not the driver
what is the link between the gut peptides, Ghrelin, and puberty
- Opposes action of leptin, senses the fasted state to stimulate feeding and fat deposition
- A bolus of ghrelin stimulates the GH/IGF axis via GHSR (Growth Hormone Secretagogue Receptor)(Ghrelin receptor)
- In starvation (high ghrelin) decreases the activity of the HPG axis
- Ghrelin can decrease hypothalamic kiss1 expression in rat
- Subset of kiss1 neurons in selective hypothalamic nuclei that express GHSR and respond to Ghrelin.
- Ghrelin decreases as puberty proceeds
- Oestradiol can also increase GHSR expression and response to Ghrelin in kiss1 neurons (Frazzao et al, 2014)
- No conclusive evidence that Ghrelin is key hormone in regulating puberty
Does Kisspeptin drive the onset of puberty?
- ¾ of the GnRH neurons co-express Kiss1r mRNA= there is co-localisation between the two
- Kisspeptin receptors are expressed on GnRH neurones
At puberty, there is an upregulation of kisspeptin mRNA expression. However, there is no change in the expression of the kisspeptin receptor.
Continuous infusion of kisspeptin causes initial LH release in monkeys and then there is a decrease.
When pulsatile kisspeptin is administered = pulsatile release of LH
What are the observations of Kisspeptin KO mice/Humans (mutations)?
o Abnormal development of GnRH neurones
o Failure to enter puberty
o KO mice for GPR54 or kisspeptin = hypothalamic hypogonadism
o Mutations in humans = hypothalamic hypogonadism
o Phenotype (mice) – hypothalamic hypogonadism Male: small testes & epididymis, delayed spermatogenesis, infertility Female: small oviducts, folliculogenesis – no progression to ovulation, no oestrous cycles, infertility
o Activating mutations of GPR54 = precocious puberty
What drives kisspeptin?
- Within fasting state in pubertal mouse that starvation decreased number of kisspeptin positive cells – shows nutritional status does impact on HPG axis via kisspeptin
- In adults – no impact = shows that it is critical for regulating puberty onset
Only in pubertal mice is the level of expression markedly reduced; not in the adult mice
Integration of Kisspeptin-GnRH system with metabolic cues:
• 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
