HPG - axis Flashcards
What do we need to reproduce?
- Correct process of sex determination (genotypic sex) and differentiation (phenotypic sex)
- Sexual maturation- Puberty
- Production and storage of sufficient supply of eggs & sperm
- Correct number of chromosomes in egg and sperm
- Actual sexual intercourse! Egg & sperm have to be transported and meet
- Fertilisation, implantation, embryonic and placental development
- Once delivered, to nurture individual until capable of “independent” life
How is HPG axis the master controller of reproduction?
Gonadal function is controlled via feedback by: Hypothalamic & pituitary peptide hormones. Gonadal steroid (and peptide) hormones.
Hypothalamus (RH)
Gonadotrophin Releasing Hormone (GnRH), (kisspeptin)
Pituitary (SH)
Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
Gonad
(F) Oestradiol (E2), Progesterone (P4), (M) Testosterone, (Inhibin and activin).
Kisspeptine (KISS1/kiss1)
- Role in reproduction recently discovered – 2001 - gatekeeper of puberty
- Hypothalamic expression- ARC and AVPV
- Upstream of GnRH
- Kisspeptin neurons send projections to GnRH neurons, and binding to GPR54 expressed on GnRH neurons
Hypothalamus GnRH
- Synthesised and secreted from GnRH neurons
- Secreted in a pulsatile fashion-pulse generator orchestrated
- Hypothalamic expression- ARC and MPN (Parvocellular system)
- Binds to the GnRH receptor (GnRHR) on gonadotroph cells of the anterior pituitary to stimulate the synthesis and secretion of gonadotrophin hormones- LH and FSH.
Pulsatility
- GnRH is secreted in pulses from hypothalamus every 30-120min.
- A GnRH pulse stimulates a pulse of LH and FSH secretion from the pituitary.
- Pulsatile GnRH secretion is vital for stimulation of LH/FSH secretion.
- Slow frequency pulse favours FSH release, rapid pulse frequency favours LH.
- Continuous release results in cessation of response.
Therapeutic application of GnRH
• Synthetic GnRH – same structure as endogenous GnRH
- pulsatile administration Stimulatory
• GnRH analogues – modified GnRH peptide structure
- Single bolus, long half life, loss of pulsatility Inhibitory
- Agonists or antagonists
Pituitary to Gonads
Ultimate coordination of gonadal function to facilitate viable gamete production (male), growth and development
Gonadotrophin hormones: LH, FSH (hCG)
Heterodimeric peptides – common α-subunit and hormone-specific β-subunit
• N-linked carbohydrate side chains required for biological function
• Free subunits have no biological action
• α-subunits are synthesized in excess with β-subunit limiting the hormone concentration
Pulsatile secretion due to pulsatile GnRH release from hypothalamus but pulsatile secretion not necessary for biological activity
Luteinising hormone
• Testis:
- stimulation of Leydig cell androgen synthesis
• Ovary:
- theca cell androgen synthesis
- ovulation
- progesterone production of corpus luteum
Follicle-stimulating hormone
• Testis: - regulation of Sertoli cell metabolism • Ovary: - follicular maturation - granulosa cell estrogen synthesis
Oestrogens
- Oestradiol and also oestrone
- Folliculogenesis
- Positive feedback triggers ovulation
Androgens
- Androstenedione, testosterone, dihydrotestosterone
- Spermatogenesis
Progesterone
- Prepares the uterus for implantation
- Maintains conditions required for the early stages of pregnancy
Puberty
- Transition from non-reproductive to reproductive state
- Breast development in females, and increased testicular volume in males.
- Secondary characteristics develop (primary are present at birth)
- Profound physiological changes
- Profound psychological changes
Adrenarche
• Change in adrenal androgen secretion due to cellular remodelling of adrenal gland.
- Dehydro-epiandrosterone (DHEA)
- Dehydro-epiandrosterone sulphate (DHEAS)
No change in other adrenal steroids
- Secreted from zona reticularis of adrenal cortex
- No known mechanism for trigger of adrenarche
Pubarche
Appearance of pubic / axillary hair resulting from adrenal androgen secretion
Associated with:
sebum production = acne
Infection, abnormal keratinization = acne
If before 8 years (girls) or 9 years (boys)
= PRECOCIOUS
Gonadarche
- Several years after adrenarche (typically ~11 yrs of age)
- Reactivation of hypothalamic GnRH
- Activation of gonadal steroid production production of viable gametes and ability to reproduce
Gonadarche:GnRH
GnRH is synthesised & secreted by specialist hypothalamic centres – GnRH neurones.
HPG axis is first activated at 16th gestational week
• Pulsatile GnRH secretion in foetus until 1-2 years postnatally when ceases
• Re-activation at ~11 years
GnRH neurones ‘restrained’ during postnatal period 10 years or more
At puberty a gradual rise in pulsatile release of GnRH
Onset of puberty theories
Clear that it is maturational event within the CNS
• Inherent (genetic) maturation of 800-1000 GnRH synthesising neurones?
• Environmental/genetic factors?
• Body fat/nutrition?
• Kisspeptin?
Nutrition & body fat
• Link between fat metabolism & reproduction
• Anorexia nervosa / intensive physical training
Reduced response to GnRH
↓gonadotrophin levels
Amenorrhea
Restored when nourished / exercise stopped
• Frisch et al.: body fat hypothesis
Certain % fat:body weight necessary for menarche (17%) & required (22%) to maintain female reproductive ability
Kisspeptin and puberty
- Inactivating mutations of KISS1R or the gene coding for kisspeptin
- Hypogonadism
- Failure to enter puberty
- Hypogonadotrophic hypogonadism
- Activating mutations of KISS1R
- Precocious puberty
Tanner stages of puberty
- Pubic and axillary hair growth (♀♂)
- Testicular volume and penile length (♂)
- Breast development (♀)
Physical changes in girls during puberty part 1
Breasts enlarge
thelarche – first outward sign of E2 activity
Pubic/axillary hair
Uterus enlarges, cytology changes, secretions in response to E2
Uterine tubes
Cervical changes
Physical changes in girls during puberty part 2
• Height
- earlier onset than boys
- peak height velocity (PHV) = 9 cm/y, reached at 12 yrs
• Body shape
• HPG axis
- increase in ovarian size and follicular growth
• Menarche
- not equated with onset of fertility
• Fertility
- in 1st year ~80% menstrual cycles anovulatory, irregular cycles
Physical changes in boys during puberty 1
• External genitalia - increase in testicular volume >4 ml • growth of penis, scrotum, scrotal skin changes • Vas deferens • lumen increases • Seminal vesicles & prostate • Facial/body hair • Pubic / axillary hair
Physical changes in boys during puberty 2
• Larynx – androgens enlarge larynx, Adams apple (projection of thyroid cartilage), voice deepens • Height PHV =10.3 cm/y reached at 14 yrs • Body shape • Onset of fertility testosterone from Leydig cells stimulates meiosis & spermatogenesis in Sertoli cells Boys fertile at the beginning of puberty
Psychological changes of puberty
- Increasing need for independence
- Increasing sexual awareness/interest
- Development of sexual personality
Later maturation = better adjustment
Biphasic effect of oestrogen on ephiphyseal growth
Low levels = linear growth & bone maturation
High levels = epiphyseal fusion
Growth interaction
Complex interaction
Growth hormone
Oestrogen (boys and girls)
Earlier in girls – approx. 2 years
Precocious sexual development
Development of any secondary sexual characteristic
Before the age of 8 in girls
Before the age of 9-10 in boys
Gonadotrophin-dependent (or central) precocious puberty
consonance
Excess GnRH secretion - idiopathic or secondary
Excess gonadotrophin secretion - pituitary tumour
Gonadotrophin-independent precocious puberty
loss of consonance
Testotoxicosis - activating mutation of LH receptor
Sex steroid secreting tumour or exogenous steroids
Constitutional delay
affecting both growth and puberty. Approx. 90% of all pubertal delay cases.
~10X more common in boys
secondary to chronic illness e.g., diabetes, cystic fibrosis
Hypogonadotrophic
(low LH and FSH)
Kallman’s syndrome (X-linked KAL1 gene, impaired GnRH migration),
Other mutations causing defects in GnRH production
Hypergonadotrophic hypogonadism
(high LH and FSH)
Gonadal dysgenesis and low sex steroid levels:
gonadal dysgenesis with normal karyotype, viral e.g. mumps
