Puberty Flashcards
Puberty
Is a complex developmental event
It is a continuum of changes leading to somatic and sexual maturation
There are profound physiological, psychological and physical changes
The main reproductive goal is to produce mature gametes:
Testes 🡪 spermatozoa
Ovaries 🡪 oocyte
From a clinical perspective puberty is defined as: Breast development in females, and increased testicular volume in males (Above 4ml)
Two Endocrine Events of Puberty
1st = Adrenarche
The switching on of adrenal androgens
This is responsible for the growth of pubic hair, axillary hair and height.
2nd = Gonadarche
Switching on of the HPG axis
Results in the secretion of gonadotrophins: FSH and LH
LH - steroid synthesis –> secondary sex characteristics
FSH - growth of testis (male)/steroid synthesis/folliculogenesis (female)
These two endocrine events combinate in puberty. The two events are independently regulated, so you don’t need one for the other to occur.
Adrenarche
Is the first endocrine event of puberty
Occurs at 6-8 years
Is characterised by (re-)instigation of adrenal androgen secretion:
Dehydro-epiandrosterone (DHEA)
Dehydro-epiandrosterone sulphate (DHEA-S)
Studies have shown that there is no change in cortisol/other adrenal hormones during adrenarche
It is not a global activation of HPA axis
Adrenarche- DHEA/DHEAS
DHEA/DHEAS levels start to rise at 6y
It continues to rise, there is a peak in the 20s.
After there is a gradual decline
DHEA/DHEAS secretion is from the zona reticularis
The zone reticularis is the innermost layer of the adrenal cortex
This is the result of inherent maturation of cellular compartments of the adrenal cortex. So… there is a remodelling of the adrenal cortex in order for it to be able to secrete DHEA/DHEAS.
How is DHEA/S made?
DHEA/S is made via a series of steroidogenic conversions.
Cholesterol is the original precursor, there is then a series of conversions that occur leading to the production of DHEA/S. This is done with the aid of steroidogenic enzymes.
Eg: CYP11A which is responsible for the conversion of progesterone to pregnenolone.
Eg; CYP17 20 Lyase which is responsible for DHEA production
SULT2A1 which is responsible for making DHEAS from DHEA
In an individual undergoing puberty there is an increased expression of CYP11A in the zona reticularis (progesterone -> pregnenolone)
In an individual undergoing puberty there is an increased expression of CYP17 20 Lyase in the ZR (DHEA production)
Also in an individual undergoing puberty there is increased expression of SULT2A1
Note: There is also a sideways pathway (green). This is responsible for the synthesis of glucocorticoids and mineralocorticoids.
Occurs after the initial conversion of cholesterol to pregnenolone
It is modulated by 3bHSD which converts pregnenolone and hydroxypregnenolone into the corticosteroids.
BUT in a pubertal individual, there is a significantly reduced expression of 3bHSD compared to an infant. This is because in adrenarche, this sideways pathway is shutdown to prioritise the pregnenolone to go into the production of DHEA/S.
Adrenal Remodelling
During adrenarche there is increased expression of SULT2A1 in the zona reticularis of an individual undergoing puberty. As this is responsible for DHEAS production.
During adrenarche there is a reduced expression of 3bHSD to prevent the loss of pregnanolone to the sideways pathway.
Function of the DHEA/S
DHEA is synthesised by the adrenal gland in the zona reticularis of the adrenal cortex.
It is synthesised and makes it way through the blood system where it is synthesised by peripheral tissue where it is converted into DHT.
DHT is responsible for the growth of auxiliary hair, change in skin glands and prostate secretions.
What instigates adrenarche?
ACTH
POMC
POMC-related peptides
Other factors ruled out include prolactin, IGF-1 and insulin
How does ACTH instigate adrenarche?
Dexamethasone (a synthetic corticosteroid) suppresses adrenal androgen production.
Children with ACTH receptor mutations fail to undergo adrenarche.
But, no change in ACTH/cortisol levels during adrenarche
Are there Divergent mechanisms for cortisol and androgen production at adrenarche?
How does POMC instigate adrenarche?
POMC = Pro-opiomelanocortin - 241AA sequence that undergoes cleavage into multiple peptides.
Proximal 18 AA region that positively regulated adrenal androgen production.
BUT In vitro studies did not substantiate this
How do POMC- relayed peptides instigate adrenarche?
b-lipotrophin and b-endorphin plasma levels correlate with increased DHEA/S at adrenarche
No real evidence
Gonadarche
Gonadarche is characterised by a (Re-)Activation of HPG axis.
Occurs several years after adrenarche (typically ~11 yrs of age).
Driven by hypothalamic GnRH & pituitary gonadotrophins.
Gonadarche is modulated via the HPG axis:
Hypothalamus (GnRH)–> Pituitary (Gonadotrophins: LH/FSH)–> Gonads (Steroidogenesis)
Puberty depends on..
Puberty depends on reactivation of GnRH release
HPG Axis and Puberty
During the 16th gestational week of development, there is activation of HPG axis for the first time.
There is pulsatile GnRH secretion in foetus
This continues until just before birth, where it is switched off.
It is believed to be switched off to make way for the feedback from the placental hormones.
Then after birth the HPG axis is switched on again for 1-2 years postnatal increased.
Believe it is switched on again after birth as a priming of the HPG axis.
It is then switched off again
In the week 12 pregnancy scan, you cannot determine the sex of the baby, but in the week 20 scan you can.
This is because of the 16th week activation of the HPG axis which is required for completion of sexual differentiation.
After the axis is switched off after the postnatal period, we believe that the Neurones ‘restrained’ during postnatal period 🡪 10 years or more
At puberty there is a gradual rise in pulsatile release- around 1 year before breast budding observed
The reactivation usually begins with a nocturnal rise in GnRH levels;
A you progress through puberty you start to have more consistent levels throughout the day.
HPG axis summary
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
Consonance and Tanner Stages of Puberty
Everybody progresses from stage 1->5. This movement through the stages is called consonance.
BUT what will differ is the time spent in each stage and the time it takes to move from one stage to another.
The tanner stages are a useful tool to detect when puberty is not in consonance.
Onset of puberty (current theories)- Potential adverse risks from early puberty:
cardiovascular disease
metabolic disease
obesity
diabetes
disordered behaviour
In early puberty you have a case where a person undergoes sexual maturation before mental maturation.
decreased adult height
Bone fusion occurs earlier than it should
decreased life expectancy
What controls the onset of puberty?
It’s a dialogue between our individual genetics and environmental factors
They 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?
Epigenetics is changes in the expression of a gene, changes in the phenotype without any changes in the structure. These changes in expression can be passed to offspring.
Over the past 100 years there is a uniform decrease in the age of onset of puberty (17 -> 13)
Now we are better fed, more lethargic.
This suggests a link between energy homeostasis and reproduction.
Role of nutrition and body fat in 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
Frisch et al.: “critical fat mass” hypothesis
Threshold % fat/body weight is required to attain (17%) and maintain female reproductive ability (22%)
As pregnancy is an energy intensive process.
There is cross talk between metabolic status and puberty onset/maintenance of reproduction
Nutritional Gating and Puberty
Based on evidence available we believe that secretions from the gut and secretions from adipose tissue act on the hypothalamus and in turn modulate gonadal function via the HPG axis.
Adipose tissue: leptin (mouse model)
In 1950s a mouse was isolated for its erratic behaviour, after tests they found the mouse was:
Hyperphagic
Hyperglycaemic
Insulin resistant
Infertile
Leptin deficient – Mutation in gene coding for leptin
Leptin Role
1994: leptin gene first cloned
Expressed in adipocytes- WAT (white adipose tissue)
Is a sensor of energy sufficiency
It is a satiety factor - tells brain you’re full
It stimulates energy expenditure
The circulating levels of leptin are directly proportional to amount of body fat
Effect of Leptin on Repro system
In most common forms of obesity, the leptin receptor does not respond properly to the leptin signal.
Influence on reproductive system
ob/ob mice & humans present with hypogonadotrophic hypogonadism
Delayed/absent puberty
BUT Can be reversed with leptin injection
Some leptin-deficient patients have normal menses/LH/oestradial levels- and it is unknown why.
