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.

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.

- Oestradiol and also oestrone - Folliculogenesis - Positive feedback triggers ovulation

- Androstenedione, testosterone, dihydrotestosterone - Spermatogenesis

- Prepares the uterus for implantation - Maintains conditions required for the early stages of pregnancy

HPG - axis Flashcards by Rorleen Matemba

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

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How is HPG axis the master controller of reproduction?

Gonadal function is controlled via feedback  by:
Hypothalamic &amp; pituitary peptide hormones.
Gonadal steroid (and peptide) hormones.

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Hypothalamus (RH)

Gonadotrophin Releasing Hormone (GnRH), (kisspeptin)

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Pituitary (SH)

Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)

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Gonad

(F) Oestradiol (E2), Progesterone (P4), (M) Testosterone, (Inhibin and activin).

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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

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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.

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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.

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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

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Pituitary to Gonads

Ultimate coordination of gonadal function to facilitate viable gamete production (male), growth and development

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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

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Luteinising hormone

• Testis:
- stimulation of Leydig cell androgen synthesis
• Ovary:
- theca cell androgen synthesis
- ovulation
- progesterone production of corpus luteum

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Follicle-stimulating hormone

• Testis:
	- regulation of Sertoli cell metabolism
• Ovary: 
	- follicular maturation
	- granulosa cell estrogen synthesis

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Oestrogens

Oestradiol and also oestrone
Folliculogenesis
Positive feedback triggers ovulation

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Androgens

Androstenedione, testosterone, dihydrotestosterone

- Spermatogenesis

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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

1. Pubic and axillary hair growth (♀♂) 2. Testicular volume and penile length (♂) 3. 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

1. Increasing need for independence 2. Increasing sexual awareness/interest 3. 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