HPG Axis and Puberty Flashcards
What are the 3 levels of the HPG axis in puberty?
H: hypothalamus releases GnRH from neurosecretory neurons stimulated by kisspeptin
P: pituitary releases FSH/LH (gonadotrophin)
G: gonads synthesise and release ESTRADIOL (E2) and PROGESTERONE (P4) (E2 +P4 are predominant in females) and TESTOSTERONE (predominant in males)
N.B. that all 3 sex hormones are produced by both sexes
What is kisspeptin?
peptide hormone
10-54aa in size
kisspeptin neurons send projections to GnRH neurones
GnRN neurons contain kisspeptidn receptors - binding causes release of GnRH
What is GnRH and where it is released?
small, 10aa peptide hormone
released by neurons into the median eminence
travels to anterior pituitary via the HYPOPHYSEAL PORTAL VESSEL
binds to GnRH-receptors on gonadotroph cells
These then produce LH/FSH
Where is the superior hypophyseal artery?
connection between the hypothalamus and pituitary
type of portal vessel
delivers blood into capillary network of upper infundibulum
allows access to the anterior pituitary for subsequent activation
What fo the role of the hypophyseal veins?
carry blood containing pituitary hormones
carried to cardiovascular system for systemic delivery
What blood vessel delivers blood to the posterior pituitary?
inferior hypophyseal artery
What is the nature of GnRH secretion? Why is this important?
GnRH has PULSATILE secretion
every 30-120mins
GnRH receptor is a GPCR
continuous secretion switches off the HPG axis
What types of GnRH stimulates LH/FSH secretion?
SLOW GnRH: FSH release
FAST GnRH: LH release
What are the generalised structure of gonadotrophins?
heterodimeric peptides
common alpha subunit (92aa) and hormone-specific beta subunit
beta subunits are less abundant and therefore regulate the specific [hormone]
What is the structure of LH?
common alpha subunit (92aa)
LH beta subunit (121aa)
What is the structure of FSH?
common alpha subunit (92aa)
FSH beta subunit (110aa)
What is the structure of hCG?
common alpha subunit (92aa)
hCG beta subunit (145aa)
What post-translational modifications allow full biological potency of the gonadotrophin?
LH/FSH: N-linked glycosylation
hGH: O-linked glycosylation
=> function may vary through pregnancy/menstrual cycle
note that free subunit monomers carry no biological function
What are the 2 main endocrine events in puberty?
- Adrenarche + Pubarche
- Gonadarche
(together make up puberty, but are independently regulated)
What is adrenarche?
change in adrenal secretion
caused by adrenal gland remodelling from childhood
ZONA RETICULARIS: develops as independent zone as adrenarche occurs
secretion of DHEA (sulfated and non-sulfated) lead to pubarche
[at 10-20yo]
What are the proposed triggers for adrenarche?
largely unknown
leptin or insulin signalling
may be related to body mass
physiological remodelling of adrenal glands
What are the main stages of puberty?
- ADRENARCHE maturation of cells in adrenal gland
- release of androgens
- This causes PUBARCHE - appearance of pubic and axillary hair
[GONARCHE follows on from pubarche, driven by HPG axis]
- synthesis and secretion of LH/FSH
- Activation of gonadal function
- LH: gonadal steroidal synthesis and secondary sex characteristics
- FSH: testis growth (male) and folliculogenesis with steroid synthesis (female)
What is the function of DHEAS in adrenarche?
= sulfated dehydroepiandrosterone
transported to gonads/adrenals where it is converted to testosterone or DHT
occurs in Leydig cells in M
What is pubarche?
appearance of pubic or axillary hair (from androgen secretion during adrenarche)
Acne: increased sebum production
infection can be caused by abnormal keratinisation
When is pubarche considered to be ‘precocious?’
GIRLS: <8 yo
BOYS: <9yo
What are pilosebacious units?
= PSUs
= hair + hair follicle + error pills muscles + sebaceous glands
deposit sebum on hairs
bring hair to surface along the hair shaft
What does a sebaceous PSU consist of?
large sebaceous gland
secrete sebum under androgen influences
acne develops when pores are blocked or become infected
What structures go on to become moustache and beard hair?
terminal PSUs
What are villus pilosebaceous units?
can differentiate into 2 types of hair: terminal PSU or apocrine PSU
occurs under androgen exposure
What is an ECCRINE GLAND?
type of simple sweat gland
produces most sweat
not associated with hair follicles
What are APOCRINE GLANDS?
present in the skin
scent glands
secretions usually have an odour
located in the armpits and groin
go on to form pubic and axillary hair
What is GONADARCHE?
HPG axis first activates during 16th gestational week
pulsatile GnRH in foetus occurs until 1-2 years (postnatally)
GnRH neurons restrained between 2-10yo
only reactivated during gonadarche (due to pulsatile GnRH release)
increased kisspeptin promotes GnRH release
ultimately stimulates gonadal steroidogenesis
this will lead to viable gamete production
What is the best method of monitoring GnRH secretion?
Can measure serum LH levels (more accurate than FSH levels)
How does GnRH release change through puberty?
becomes a more consistent pulsatile release
in the adult, pulse frequency occurs during the day
What are the epiphyses? What is fusion?
rounded ends of bones (=growth plate)
initially form separately to the long bones, will eventually fuse with main shaft of long bone
initially low oestrogen levels promote bone growth (linear)
and mediate rapid growth spurt
then, fusion occurs when the oestrogen levels rapidly increase during puberty
What mediates the pubertal growth spurt?
complex interaction between GH and Oestrogen
occurs ~2yrs earlier in F than M
What is the relationship between oestrogen and epiphyseal growth?
low [oestrogen] = when HPG reawakens, promotes linear growth INITIAL GROWTH SPURT
high [oestrogen] = epiphyseal FUSION at growth plates GROWTH STOPS
What stimulates pubertal onset?
[not entirely known]
maturational event within CNS
- GENETIC: maturation of GnRH synthesising neurons, also epigenetic regulation
- NUTRITION: earlier puberty as neutron improves. Malnutrition delays puberty, 17-18% body fat needed to initiate puberty and 22% to maintain menstrual cycle (link to leptin levels?)
- KISSPEPTIN: variants in kisspeptin may alter puberty initiation (GoF vs LoF)
What is consonance?
= smooth ordered progression of changes in puberty
this will remain regardless of how long each pubertal transition takes
What are the physical changes that occur in BOYS during puberty?
External genitalia - increase in testicular volume >4ml growth of penis, scrotum, scrotal skin changes
Vas deferens - lumen increases.
Seminal vesicles & prostate - maturation preparation for secretion.
Facial / body hair
Pubic / axillary hair
Larynx - androgens enlarge larynx. Adams apple (projection of thyroid cartilage), voice deepens
Height - PHV = 10.3 cm/year reached at 14 years
Body shape - broadening of shoulders and chest; shoulders wider than hip.
Onset of fertility - testosterone from Leydig cells stimulates meiosis & spermatogenesis in Sertoli cells boys fertile at the beginning of puberty.
What are the physical changes that occur in GIRLS during puberty?
Breasts enlarge - thelarche – first outward sign of estrogen activity represents reawakening of HPG axis.
Pubic/axillary hair
Uterus enlarges - myometrium responds to estrogen.
Endometrium, uterine tubes, cervix - differentiation & maturation.
Height - earlier onset than boys peak height velocity (PHV) around 9 cm/year, reached at 12 years.
Body shape - widening of the hips.
Ovary - increase in ovarian size and follicular growth.
Menarche - not equated with onset of fertility but late into puberty at Tanner stage IV.
Fertility - in 1st year ~ 80% menstrual cycles anovulatory, irregular cycles.
What are the Tanner stages?
= pubertal development
stages 1 -5
stage 1: pre-pubescent, puberty starts at stage 2
stage 5: end of puberty (in F, this is marked by onset of menses)
What psychological changes occur in puberty?
- increasing need for independence
- increased sexual awareness/desire
- development of sexual personality
What is ‘central precocious puberty?’
= Gonadotropin-DEPENDENT precocious puberty
CONSONANCE MAINTAINED
- excess GnRH secretion: idiopathic or secondary
- excess gonadotrophin secretion: pituitary tumour
accelerated linear growth (for age), advanced bone growth, increased LH/FSH/E2 and testosterone
What is the Rx for central precocious puberty?
- case-by-case assessment
- dependent on age, psychological benefits, parent wishes, and expectations
GnRH analogues: suppress puberty until 11-12yo (if appropriate)
Surgery, radiotherapy or chemo also available
What is the consequence of a hypothalamic hamartoma?
found in 33% of patients with central precocious puberty
unclear aetiology, but proposed to be non-physiological GnRH secretion
HAMARTOMA = focal malformation, usually benign. resembles a neoplasm in the tissue of its origin
What is ‘peripheral precocious (pseudo) puberty’?
Gonadotrophin-INDEPENDENT peripheral precocious puberty
Hallmark: secondary characteristics develop BEFORE gonadal development
Associated with:
- suppressed LH/FSH
- elevated oestrogen and testosterone
What are the different types of peripheral precocious puberty?
TESTOXICOSIS: activating mutation in LH receptor causes early androgen synthesis 9=(in Leydig/Theca cells)
No FSH increase so no spermatogenesis
Sex steroid secreting tumour/exogenous steroids: secondary sexual characteristics
McCUNE ALBRIGHT SYNDROME: constitutive activation of adenylate cyclase. Causes hyperactivity of signalling pathways including those of gonadotrophin hormones
CONGENITAL ADRENAL HYPERPLASIA (CAH): compensatory androgen overproduction (deficient in cortisol)
What is McCUNE-ALBRIGHT SYNDROME?
rare genetic disorder
affects skins colour (cafe au lait), bones and hormone imbalance
caused by activating mutations in alpha subunit of G(as) subunit of GPCR
LH and hCG receptors: GPCR
causes autonomous endocrine function and fibrous dysplasia
What is pubertal delay?
= absence of secondary characteristics by 14yo (M) and 13yo (F) or absence of menarche by 18o (F)
What are the different types of pubertal delay?
- constitutional delay
- HYPOgonadotrophic hypogonadism (low LH/FSH)
- HYPERgonadotrophic hypogonadism (high LH/FSH)
What is constitutional pubertal delay?
affects both growth and puberty 90% of all pubertal delay cases M > F (x10 in M) polygenic can occur secondary to chronic illness e.g. DM, CF
What is HYPOgonadotrophic hypogonadism?
= low LH/FSH
KALLMANN’S SYNDROME (X-linked KAL gene: impairment of GnRH neurone migration)
Hypopituitarism, impaired gonadotrophins
high dose or long term expo to opioid or steroid medicines
other genetic disorders
What is HYPERgonadotrophic hypogonadism?
= high LH/FSH
insensitivity to LH/FSH from gonadal dysgenesis
Low sex steroid levels (low negative feedback and high gonadotrophins)
Congenital:
- KLINEFELTER’S SYNDROME (XXY sex chr) 1:500 males
- TURNER’S SYNDROME (X- sex chr) 1:3000 females
Gonadal dysgenesis with normal karyotype e.g. mumps
What are the (positive) acute phase proteins?
=>INCREASE during inflammation
- CRP
- procalcitonin
- ferritin
- alpha-1 antitrypsin
- caeruloplasmin
- serum amyloid A
- serum amyloid P component
- haptoglobin
- complement
What are the (negative) acute phase proteins?
=> DECREASE during inflammation
- albumin
- transthyretin (aka prealbumin)
- transferrin
- retinol binding protein
- cortisol binding protein
