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PHYS - REPRO > 2. HPG AXIS I > Flashcards

2. HPG AXIS I Flashcards

1
Q

What are the key organs of the HPG axis?

A
  1. Hypothalamus
  2. Pituitary
  3. Gonads (ovary or testes)
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2
Q

What’s the function of the HPG axis?

A
  • The HPG axis is involved in regulating reproductive or gonadal function in males & females
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3
Q

What hormones of the HPG axis control gonadal function?

A
  • Gonadal function is controlled by negative feedback via hypothalamic & pituitary peptide hormones & gonadal steroid hormones
  • HYPOTHALAMUS: GnRH (Gonadotrophin releasing hormone), KISSPEPTIN
  • PITUITARY GLAND: LH (Luteinising hormone) & FSH (Follicle stimulating hormone)
  • GONADS: Androgens, testosterone, oestrogen
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4
Q

Describe the steps involved in the HPG pathway from the hypothalamus to the pituitary gland

A
  1. Kisspeptin is released from kisspeptin neurones in the arcuate nucleus & anteroventricular periventricular nucleus
  2. Kisspeptin binds to GPR54 neurones in the hypothalamus
  3. The hypothalamus secretes GnRH
  4. GnRH moves through the hypophseal portal circulation via the primary plexus, hypophyseal vessel & secondary plexus
  5. GnRH binds to GnRH receptors on the gonadotrophs of the anterior pituitary
  6. Anterior pituitary releases FSH & LH into the circulation
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5
Q

What is kisspeptin?

A
  • Kisspeptin is a hormone released from hypothalamus, it acts upstream of GnRH
  • The hypothalamic expression of kisspeptin occurs in the arcuate nucleus & the anteroventricular nucleus
  • Kisspeptin binds to GPR54 receptors on the GnRH neurones of the hypothalamus to cause GnRH release
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6
Q

Describe the structure of Kisspeptin

A
  • Kisspeptin is initially synthesised as a preprotein (Prepro-kisspeptin)
  • It is then cleaved to Kisspeptin 54 (KP54)
  • KP54 -> KP14 -> KP13 -> KP10
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7
Q

Where is Gonadotrophin releasing hormone secreted from & how?

A
  • Gonadotrophin releasing hormone is secreted from the GnRH neurones of the hypothalamus in a pulsatile fashion
  • The hypothalamic expression of GnRH occurs in the parvocellular system (arcuate nucleus & medial pre-optic nucleus)
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8
Q

What does gonadotrophin releasing hormone do?

A
  • GnRH binds to GnRH receptors on the gonadotrophs of the anterior pituitary
  • GnRH stimulates the release of LH & FSH from the anterior pituitary
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9
Q

What’s the importance of pulsatile GnRH secretion?

A
  • GnRH must be released in a pulsatile fashion every 30 mins -2 hours from the hypothalamus
  • The pulsatile secretion is vital for the secretion of LH & FSH from the anterior pituitary
  • If it’s not delivered in a pulsatile fashion, GnRH secretion will stop
  • Continuous secretion of GnRH will lead to cessation of the HPG axis & the release of LH & FSH
  • Slow frequency GnRH pulse favours FSH. Rapid frequency GnRH pulse favours LH, but both will be released
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10
Q

What are the two types of GnRH used in therapeutic applications?

A
  1. Synthetic GnRH

2. GnRH analogues

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11
Q

*What is synthetic GnRH & what is it used for?

A
  • Synthetic GnRH has the same structure as endogenous GnRH. It is produced from cell cultures
  • It’s administered in a pulsatile fashion to produce a stimulatory effect
  • It is used to treat pubertal delay, disorders & deficiencies caused by mutations
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12
Q

What’s the mechanism of action for synthetic & endogenous GnRH?

A
  1. GnRH binds to GnRH receptors in anterior pituitary
  2. Activates signalling pathway & stimulates synthesis & secretion of LH & FSH
  3. GnRH dissociates from GnRH receptor as it has a short half life
  4. GnRH receptor is responsive to the next GnRH pulse
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13
Q

What is a GnRH analogue & what is it used for?

A
  • A GnRH analogue has a modified GnRH structure to give it certain properties. For example, synthetic & endogenous GnRH have a short half life, so an analogue can be modified to have a long half life. A longer half life means a higher affinity to the receptor, allowing it to outcompete endogenous GnRH
  • GnRH analogues are delivered as a single bolus, the long half life means that it can stay in the circulation for longer, mimicking continuous delivery
  • GnRH analogues have an inhibitory effect and will shut down the HPG axis so they can be used in IVF treatment
  • Shitting down the HPG axis, allows the body to respond to external FSH & LH.
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14
Q

What’s the mechanism of action for GnRH agonist analogues?

A
  1. GnRH analogue binds to GnRH receptor
  2. Activates signalling pathway & stimulates secretion & synthesis of LH & FSH
  3. The long half life of GnRH analogue means that it doesn’t dissociate, desensitising the receptor
  4. GnRH is uncoupled from the G-protein signaling pathway
  5. GnRH receptor is unresponsive to GnRH
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15
Q

What’s the mechanism of action for GnRH antagonist?

A
  1. GnRH antagonist binds to GnRH receptor

2. Blocks the GnRH receptor so that there are no downstream effects

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16
Q

What are 7 clinical uses of GnRH & GnRH analogues?

A
  1. Ovulation induction & IVF
  2. Breast cancers
  3. Prostate cancer
  4. Ovarian & endometrial cancers
  5. Endometriosis
  6. Uterine fibrosis
  7. PCOS
    - Some cancers are hormone dependent (e.g oestrogen or androgens, so shutting down the HPG axis can stop proliferation)
17
Q

What are the steps involved in the HPG pathway from the pituitary gland to the gonads?

A
  1. The anterior pituitary releases the gonadotrophins LH & FSH into the circulation
  2. LH & FSH act on the gonads
  3. The gonads release gonadal steroid & peptide hormones such as oestrogen or androgens
18
Q

Describe the structure of the gonadotrophins LH & FSH

A
  • LH, FSH & hcG are heterodimers of two subunits:
    1. Common alpha subunit (same for FSH & LH)
    2. Hormone specific beta subunit (differs for FSH & LH)
  • These subunits dimerise to form heterodimers, they are functionally inactive on their own
  • The common alpha sub-unit is produced in excess via a gene expression pathway
  • The beta subunit is synthesized based on the GnRH pulse
  • LH & FSH have N-linked carbohydrate side chains which provide biological function. Cleavage of these side chains could lead to a loss of function
19
Q

Describe the secretion of LH & FSH?

A
  • The secretion of FSH & LH is dependent on the GnRH pulse. A pulsatile GnRH secretion is vital but a pulsatile LH & FSH secretion is not
  • Slow frequency GnRH pulse = favours FSH beta subunit
  • Rapid frequency GnRH pulse = favours LH beta subunit
20
Q

What’s the function of the luteinising hormone in the testis?

A
  • Leydig cells express LH receptors

- LH binds to Leydig cells to produce testosterone

21
Q

What’s the function of the luteinising hormone on the ovary?

A
  • Theca cells express LH receptors. LH binds to Theca cells to stimulate androgen synthesis.
  • These androgens migrate to the granulosa cells to be converted into oestoigen by aromatase
  • LH surge stimulates ovulation
  • LH binds to LH receptors on the corpus luteum to produce progesterone
22
Q

What the function of FSH on the testis?

A
  • Sertoli cells express FSH receptors. FSH binds to Sertoli cells to regulate Sertoli cell metabolism & spermatogenesis
  • Androgens produced by Leydig cells migrate to Sertoli cells to be converted to Oestrogen
23
Q

What’s the function of FSH in the ovary?

A
  • Granulosa cells express FSH receptors. FSH binds to Granulosa cells to stimulate Oestrogen synthesis
  • FSH is involved in follicle maturation
  • Androgen produced by Theca cells migrate to granulosa cells to be converted to oestrogen by aromatase enzyme under the influence of FSH

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