Puberty Flashcards
Define Puberty
A complex developmental event
Continuum of changes leading to somatic and sexual maturation
Profound physiological, psychological and physical changes
What are the reproductive goals of puberty ?
To produce mature gametes (fertility):
Testes-Spermatozoa (production of sperms )
Ovaries-Oocyte (meiotically competent oocytes as females are born with their eggs already)
What clinical changes can be seen in puberty ?
In females: defined as breast development (therlarche)
In males: increased testicular volume
What are the two endocrine events of puberty?
Adrenarche
Gonadarche
What is Adrencarche ?What are some of the visual changes seen?
This is the creation of Adrenal androgens
The growth pf pubic hair and axillary hair can be seen
Growth in height
What is Gonadarche ?
This is the swithcing on of the HPG axis to produce LH/FSH.
LH causes : Steroid synthesis which leads to secondary sex charcteristics
FSH-Growth of testsis (male )/Steroid synthesis and folliculogenesis in females.
The two processes are independently regulated.
Define Adrenarche and outline its process
First endochrine process of puberty
Occours at around 6-8 years old
Characterised by reinstigation of adrenal; androgen secretion:
Dehydro-epiandrosterone (DHEA)
Dehydro-epiandrosterone sulphate (DHEA-S)
Outline the changes in levels of DEHA /DHEAS
They begin to rise at around the age of 6 years old and a decline occurs at the 20s.
Androgen secretion occurs from the zona reticularis which is the innermost layer of the adrenal cortex.
How does the adrenal cortex begin secreting DHEA/DHEAS?
This is because there is a remodelling which will take place which allows the secretion of DHEA/DHEAS.
This is also as a result of maturation of cellular compartments of the adrenal cortex.
Outline the changes in DHEAS/DHEA secretion over time
At first :
1.Foetus -The adrenal gland has two zones (Foetal zone +Definitive zone )
Secretes DHEA/DHEAS
- Neonate (Following birth)-There is an involution of the FZ which is a shrinkage.Accompanied by drop in DHEA/DHEAS.
- During the infant stage the definitive zone will expand and differentitae into the zona glomerulosa and Zona fasciciulata
(DHEA/S production is now switched off )
- During ages of 3 years old there are patches forming called focal islands of the ZR.
- There is an expanison of the ZR focal islands at around ages 4-5
- At around 6 years old there is a function ZR developed an DHEA/S production resumes.
- At age 12-13 years old the zona reticularis will expand.
What will cause Adrencarche ?
This is when DHEA/DHEAS are produced following zona reticularis remodelling.
How is DHEA/DHEAS produced?
They are produced through stereogenic conversions.
Cholesterol is the original precursor.
Cholesterol is converted into pregenolone via CYP11A
CYP17 will then convert pregenolone into 17-alpha hydroxypregnenolone .
Through CYP17 17,20 hydrolyse this will form DHEA .
This is then converetd by SULT2A1 into DHEA-sulfate.
How do expressions of different enzymes differ in different ages?
In individual undergoing puberty , increased expression of CYP11A (converts Cholesterol into pregnenolone) in zona reticularis compared to in an infant.
CYP17 17,20 hydrolyse increased expression in puberty in zona reticularis.
Sideways pathway responsible for synthesis for glucocorticoid and mineralocorticoids.
pregnenolone
How are corticoisteroids synthesised through the DHEA/S pathway?
When cholesterol is converted into pregnenolone, these are then directed by 3BHSD into glucocorticoids and 17-alpha hydroxypregnenolone is converted into mineralcorticoids.
How does the expression of 3BHSD differ in a pubertal individual in comparison to a infant?
This is because the progenolone and 17-alpha hydroxypregnenolone are not lost through the sideways pathway and are commited to creating DHEA/S.
Outline the immunohistochemistry of the adrenal cortex in early adrenarche.
During Adrenarche there is an increase of SALT2A1 in the zona reticularis which is responsible for DHEAS production. There is also a switched off expression of 3BHSD to focus on the DHEA?S pathway.
What are the functions of DHEA/S?
It is synthesised by the adreanl gland in the zona reticularis of the adrenal cortex.
By peripheral tissue where it is converted into DHT.
It is responsible for the growth of pubic ,axillary hair and maturation of hair follicles.
Prostate secretions + changes to skin gland s
Discuss some of the hormones/genes thought to instigate Adrenarche and arguments against them
ACTH
(Adrenocorticotrophic hormone)
1.ACTH
Dexamethosone (synthetic glugocorticosteroid) suppresses adrenal androgen production -suppresses ACTH secretion
Children with ACTH receptor mutations were found to fail to undergo adrenarche.
However it was found that no change in ACTH/cortisol took place during adrenarche.
There are potential divergent mechanisms for cortisol and androgen production at adrenarche.
2.POMC
(Protein Coding gene)
Pro-opiomelanocortin -241AA sequence that undergoes cleavage into multiple peptides
Proximal 18 AA region that positively regulates adrenal androgens production
However in vitro studies did not support this
- POMC-related peptides
- b-lipoprotein and b-endorphin plasma levels correlate with increased DHEA/S at adrenarche
Prolactin,IGF-1,Insulin
Premature pubarche in girls linked to low birth weight, hyperinsulinemia and ovarian hyperandrogenism.
Adrenal androgens highest in small for gestational age babies, with rapid childhood weight gain.
What does ACTH do ?
This is a hormone which stimulates the production of cortsiol
What is Gonadarche?
This is the (re)-activation oif the HPG axis
This occours at around 11 years of age
Driven by hypothalamic GnRH and pituitary gonadotrophin
Puberty depends on reactivation of GnRH release.
What are some changes which can occour at puberty ?
Males -Changes in voice ,increased muscle tissue ,more axillary hair ,enlargement of genitalia
Females-Wider hips, mensturation, budding,pubic and axillary hair
What happens to the HPG axis during gonardarche ?
GnRH is synthesised and secreted
Synthesis and secretion of pituitary gonadotrophin (LH and FSH)
Gonadal steroid production
Negatively/Positively feedback onto hypothalamus-pituitary to regulate GnRH and LH/FSH
How does the HPG axis reactivate during Gonadarche?
16th gestational week activation of HPG axis.
Pulsatile GnRH secretion in foetus and 1-2 years postnatal increased.
GnRH neurones ‘restrained’ during postnatal period until reactivation🡪 10 years or more.
(no definitive answer as to why it switches back on)
At puberty, a gradual rise in pulsatile release of GnRH - around 1 year before physical signs i.e. breast budding observed in females.
Why can we determine the gender of the baby at the 20th week scan but not the 12th week scan?
This is because the 16th gestational week activation of the HPG axis is required to complete sexual differentiation.
What leads to the reactivation?
During early-mid puberty, a nocturnal rise in GnRH (LH) begins to appear. As puberty progresses from mid-late puberty, GnRH pulsatile pattern appears throughout the day.
Outline consonance and the tanner stages of puberty
All individuals will progress through the different stages of puberty in the same order – this is called consonant growth. However, the onset and duration of each stage will vary between individuals. If consonant growth is not present, the individual has a disorder of puberty.
The stages of development are outlined by the tanner stages
First menstrual cycles are anovulatory
What is a difference in the onset of fertility in males and females according to the tanner stage ?
Menarche (Menstruation) in females will begin around tanner stage 4
Sperm production however in men will begin at around tanner stage 2
What are the risks of precocious (early) puberty?
Cardiovascular Metabolic disease Obesity Diabetes Disordered behaviour Decreased adult height Decreased life expectancy
What are some theories about the controls of onset of puberty ?
Inherent genetically driven maturation of CNS (GnRH secreting neurons in hypothalamus).
Body fat/nutrition – Leptin and Ghrelin
Hypothalamic hormones- Kisspeptin, other hypothalamic factors
Epigenetics-changes in expression in gene without changes to structure
Specific micro-RNAs that can regulate the start of puberty
Discuss how nutrition and body fat can impact the timing of 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.
Threshold % fat/body weight is required to attain (17%) and maintain female reproductive ability (22%).
This hypothesis makes sense because there will be energy reserves available which can protect the baby and sustain them
Cross talk between metabolic status and puberty onset / maintenance of puberty
Discuss the adipose tissue and the role of leptin in obesity/puberty
Leptin is expressed in adipocytes, it is a sensor of energy sufficiency i.e. a satiety factor that tells the brain that you’re full, it stimulates energy expenditure, it’s circulating levels are directly proportional to amount of body fat and has an influence on the reproductive system.
Obese humans deficient of leptin display hypogonadotrophic hypogonadism(condition in which the male testes or the female ovaries produce little or no sex hormones.)
They have delayed/absent puberty that can be reversed with leptin injection. However, there are some patients that have normal menses/LH/oestradial levels- unknown why.
Is leptin the trigger to puberty?
Discuss this
Sexual dimorphism ( difference in form between individuals of different sex in same species i.e. males vs females
In females there is a rise at around 2 years prior to puberty (increased GnRH pulsatility)
Males -There is no rise
Obesity increases leptin and earlier puberty occurs.
Knock out leptin in rodents/humans led to delayed/absent puberty
However the administration of leptin will not stimulate early puberty
There are no leptin receptors on GnRH neurons so leptin is not having a direct effect on GnRH production.
Likely to be a
threshold of leptin required to be reached for puberty but not a driver of puberty itself.
Outline the roles of Ghrelin
Ghrelin is a gut peptide
Ghrelin senses the fasted state, to stimulate feeding and fat deposition.
A bolus of ghrelin stimulates the GH/IGF axis (Growth hormone /insulin-like growth factor axis is a system regulating linear growth in children )
via GHSR – (growth hormone secretagogue receptor)
Important in bone growth and fusion in puberty.
In ‘starvation’ (high ghrelin) decreases activity of the HPG axis.
Ghrelin decreases as puberty proceeds.
Ghrelin can decrease hypothalamic kiss1 expression in rats
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.
Low levels of leptin and high levels ghrelin 🡪 Decreased LH
GH/IGF axis arew responsible for bone growth
Outline how Kisspeptin can be involved in puberty
Co-expression of GnRH MRNA with Kiss1R mRNA in the medial preoptic area
GnRH-MRNA expressing cells are found together
The Kisspeptin itself rather than the receptor
What happens when continuous kisspeptin infusion occours?
Effect of continuous kisspeptin infusion on LH release in juvenile rhesus monkeys. Continuous Kisspeptin infusion resulted in an LH initial surge then a rapid decrease and near cessation of response.
What is the effect of pulsatile kisspeptin administration?
Effect of pulsatile kisspeptin administration on LH secretion in juvenile monkeys.
Pulsatile administration of Kisspeptin resulted in pulsatile LH release with each bolus of Kisspeptin resulting in a surge of LH.
What result did mutations in GPR4 have?
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 GPR 54 🡪 precocious puberty
Phenotype (mice)…
Male: small testes and epididymus, delayed spermatogenesis infertility;
Female: small oviducts, folliculogenesis, no progression to ovulation, no oestrous cycles, infertility
What are some metabolic effects on Kisspeptin?
Reduced leptin in starvation, decreased kiss-1 expression therefore 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
There are indirect and direct mechanisms of Leptin action in hypothalamus on HPG axis
