Puberty Flashcards
What is puberty?
A series of complex developmental changes leading to somatic and sexual maturation
Profound physiological, psychological and physical changes
Reproductive perspective: goal to produce mature gametes:
What are the major physiological changes that occur during puberty?
Testes 🡪 spermatozoa
Ovaries 🡪 oocyte
Breast development in females
Increased testicular volume in males
What are the 2 endocrine events of puberty?
- adrenarche
- gonadarche
What changes occur in adrenarche?
Growth of pubic hair, axillary hair
Growth in height
What are the roles of LH during gonadarche?
steroid synthesis –> development of secondary sex characteristics
What are the roles of FSH in gonadarche?
Growth of testis (male)/steroid synthesis/folliculogenesis (female)
When does adrenarche occur?
First endocrine process of puberty
Occurs ~6-8 years
What are the signs of adrenarche?
Characterised by (re-)instigation of adrenal androgen secretion
- DHEA
- DHEA-S
No change in cortisol/other adrenal hormones - not a global activation of HPA axis
Where are DHEA/DHEAS secreted from during adrenarche?
Androgen secretion is from zona reticularis
What causes the release of DHEA/DHEAS from the adrenal cortex?
Result of inherent maturation of cellular compartments of adrenal cortex.
When does DHEA/S secretion begin?
Surge from around ages 6-8, Peak at mid 20s and then a decline.
Describe the maturation of the adrenal cortex causing onset of adrenarche
Remodelling of adrenal cortex occurs; causes secretion of androgens
What are the 2 zones of the fetal adrenal cortex?
Fetal adrenal gland consist of 2 zones:
- Foetal zone
- Definitive zone
How does adrenarche stop?
Initially foetal zone responsible for DHEA/S production but evolution causes shrinkage of foetal zone (↓DHEA/s)
Definitive zone enlarges and differentiates into zona glomerulosa and zona fasciculata (DHEA/S production stopped)
How are adrenal androgens reactivated in the zona reticularis?
Focal islands of zona reticularis tissue which expand and form a continuous and functional ZR layer ~6 adrenal androgens are reactivated - beginning of adrenarche (↑DHEA/S)
Outline the formation of DHEA/S
Cholesterol precursor of steroids
Converted into progenolone via CYP11A
CYP17 and Lyse 17,20 converts into DHEA/S
How does CYP protein expression differ during adrenarche?
CYP11 and CYP17 expression upregulated in individuals undergoing adrenarche compared to at infancy
What is the role of the 3bHSD enzyme?
3bHSD responsible for converting pregnenolone and DHEA/S into mineralocorticoids and glucocorticoids (cortisol ACTH etc.)
Describe the expression of 3bHSD during adrenarche
During adrenarche 3bHSD expression is switched off to ensure all Pregnenolone, cholesterol and DHEA/S is committed to adrenarche
What are the functipns of DHEA/S?
Metabolism within peripheral tissue - production of DHT
Drives maturation of hair
follicles required for growth of pubic and auxiliary hair.
Also aids prostate secretions
What is the effect of dexamethasone on adrenarche?
Dexamethasone suppresses adrenal androgen production - reduced ACTH
How is adrenarche stimulation affected in children with ACTHr mutations?
Children with ACTHr mutations fail to undergo adrenarche.
But they have no change in ACTH/cortisol during adrenarche
Divergent mechanisms for cortisol and androgen production at adrenarche?
What is POMC?
Proopiomelanocortin
Proximal 18 AA region that positively regulated adrenal androgen production
- no studies show POMC is responsible for adrenacrhe
What evidence supports the idea POMC-related peptides may affect adrenarche?
b-lipotrophin and b-endorphin plasma levels correlate with increased DHEA/S at adrenarche
What controls the onset and regulation of adrenarche?
No conclusive mechanism for control of adrenarche
What is gonadarche?
(Re-)Activation of HPG axis
When does gonadarche occur?
Several years after adrenarche (typically ~11 yrs of age).
What drives gonadarche?
Driven by hypothalamic GnRH & pituitary gonadotrophins.
Puberty depends on reactivation of GnRH release
When is the HPG axis first initiated?
16th gestational week activation of HPG axis.
Pulsatile GnRH secretion in foetus and 1-2 years postnatal increased.
How does the HPG axis become quiescent?
Neurones ‘restrained’ during postnatal period 🡪 10 years or more
When does GnRH release begin to increase again?
At puberty a gradual rise in pulsatile release- around 1 year before breast budding observed
How can GnRH levels be measured?
Serum levels of LH used as a measure of GnRH
Describe the different levels of GnRH secreted throughout different pubertal phases
Early-mid puberty
- Nocturnal rise in GnRH (LH)
Mid-late puberty
- Pulsatile release GnRH throughout day
Adult
- sustained pulsatile release of GnRH, Females have cyclic changes
According to Tanner stages, when does menarche begin?
Menarche doest start til Tanner stage 4 - fertility doesn’t kick in til ~1 yr later as reproductive system still getting used to new role for follicular maturation and selection
At what tanner stage does sperm production begin?
Sperm production in males begins at Tanner stage 2
What are the potential adverse risks of precocious puberty?
- cardiovascular disease
- metabolic disease
- obesity
- diabetes
- disordered behaviour
- decreased adult height
- decreased life expectancy
what factors control onset pf puberty?
Dialogue between our individual genetics and environmental factors
All impinge at different points of the HPG axis
What are the theories of precocious puberty?
- Inherent maturation of CNS
- Body fat/nutrition: Leptin + Ghrelin?
- Hypothalamic hormones: Kisspeptin, other factors?
- Latest theories - Epigenetics?
What is the effect of energy extremes on puberty?
Extremes of energy excess (body fat mass) impact the timing of puberty in both sexes - particularly females
What is the effect of nutrition on puberty onset?
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
How do nutritional signals effect the HPG axis?
Secretions from the gut and adipose tissues act upon the hypothalamus which regulates gonadal function via the HPG axis
What are the key nutritional signals involved in puberty?
Key secretions involved are leptin and ghrelin
Describe the pathologies of ob/ob leptin deficient mice
Hyperphagic Hyperglycaemic Insulin resistant Infertile Leptin deficient
Where is leptin expressed?
Expressed in adipocytes- White Adipose Tissue
Sensor of energy sufficiency
Satiety factor - tells brain you’re full
Stimulates energy expenditure
How do levels of leptin correlate with body fat?
Circulating levels directly proportional to amount of body fat
Leptin deficient
- brain doesn’t receive satiety signal so continue eating
Receptor is desensitised to leptin
- don’t receive satiety signal
What are the effects of leptin deficiency on puberty?
ob/ob mice & humans - hypogonadotrophic hypogonadism
Delayed/absent puberty
Can be reversed with recombinant leptin injection
Some leptin-deficient patients have normal menses / LH / E2 levels - unknown why.
How does leptin affect puberty onset in males and females?
Sexual dimorphism:
- Females- rise ~ 2 years prior to puberty (increased GnRH pulsatility)
- Males- no rise
How does obesity affect levels of leptin?
Obesity increases leptin and earlier puberty occurs
What are the conclusive effects of leptin so far?
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’
What is the role of ghrelin
Ghrelin senses the fasted state, to stimulate feeding and fat deposition.
- appetite stimulating hormone
What is the effect of ghrelin on the hypothalamic-pituitary?
A bolus of ghrelin stimulates the GH/IGF axis Via Growth Hormone Secretagogue Receptor GHSR.
How does ghrelin affect HPG axis?
In ‘starvation’ (high ghrelin) decreased activity of the HPG axis.
How do ghrelin levels change in puberty?
Ghrelin decreases as puberty proceeds
What are the effects of ghrelin on Kisspeptin?
Ghrelin can decrease hypothalamic kiss1 expression in rats (Forbes et al., 2009).
Subset of kiss1 neurons in selective hypothalamic nuclei that express GHSR and respond to Ghrelin.
Describe the relationship of GnRH and KISS1R
Co-expression of GnRH mRNA with Kiss1R mRNA in rats from the medial preoptic area.
What is the role of kisspeptin in puberty?
Kisspeptin directly stimulates GnRH activity
Proves activity of kisspeptin upstream of GnRH
GnRH activity reactivated in puberty and modulated by kisspeptin activity
What disorders were present in mice with KISS1r deficiency?
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
Phenotypically what are the characteristics associated with KiSS1r/GPR54 deficiency in males and females?
Male: small testes and epididymis, delayed spermatogenesis infertility;
Female: small oviducts, folliculogenesis-no progression to ovulation, no oestrous cycles, infertility
How does nutrition affect kisspeptin release during puberty?
Only in pubertal mice is the level of kisspeptin expression markedly reduced; not in the adult mice during fasting state
Outline the integration of metabolic cues and kisspeptin-GnRH system
- 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
