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Reproduction (Physiology 2) > Hypothalamic/Pituitary/Gonadal Axis I > Flashcards

Hypothalamic/Pituitary/Gonadal Axis I Flashcards

1
Q

What are the requirements needed for successful reproduction to occur?

A
  • Correct process of sex determination (genotypic sex) and
    differentiation (phenotypic sex)
  • Sexual maturation - Puberty
  • Production and storage of sufficient supply of eggs &
    sperm
  • Correct no. of chromosomes in egg and sperm
  • Actual sexual intercourse!
  • Fertilisation, implantation, embryonic and placental
    development
  • Once delivered, to nurture individual until capable of
    “independent” life
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2
Q

Why is sexual intercourse required for fertilisation?

A

Egg & sperm have to be transported and meet

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3
Q

How can fertilisation occur without intercourse?

A

Fertilisation can occur without sexual intercourse (e.g. IVF and other assistive reproductive treatments)

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4
Q

What is the master controller of Reproduction?

A

Master Controller of Reproduction

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5
Q

What hormones control gonadal function?

A

Gonadal function is controlled by negative feedback by:

  • Hypothalamic & pituitary peptide hormones
  • Gonadal steroid (and peptide) hormones
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6
Q

What are the hormones of the HPG axis originating in the hypothalamus?

A

Hypothalamus (RH) (hypothalamic hormones)
- Gonadotrophin Releasing Hormone (GnRH) and
(kisspeptin)

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7
Q

What are the pituitary hormones involved in the HPG axis?

A

Anterior Pituitary (SH) (peptide hormones)
- Follicle Stimulating Hormone (FSH) and Luteinising
Hormone (LH)

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8
Q

What gonadal hormones take part in the reproductive HPG axis?

A

Gonad (steroid hormones)
- (F) Oestradiol (E2), Progesterone (P4), (M) Testosterone,
(Inhibin and activin)

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9
Q

Outline how the reproductive hormones of the HPG axis aid reproduction?

A
  1. Positive drive for GnRH from hypothalamus
  2. GnRH acts on gonadotroph cells of anterior pituitary
  3. Gonadotroph cells synthesis LH and FSH
  4. LH & FSH bind and act on their gonadal receptors
  5. Gonads secrete oestrogen, progesterone and
    androgens which feedback to the anterior pituitary and
    hypothalamus in a negative fashion
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10
Q

When does positive feedback occur in the reproductive HPG Axis?

A

Positive feedback occurs during ovulation in females due to oestrogen triggering an LH surge

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11
Q

What is the significance of the reproductive HPG Axis?

A

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

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12
Q

What is the hypothalamic-hypophyseal portal system?

A

This is a network of blood vessels transporting GnRH from hypothalamus to anterior pituitary `

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13
Q

Why is there such a large number of neurons in the hypothalamus?

A

The hypothalamus has many functions ∴ has many different neurons secreting various hormones

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14
Q

How is GnRH found in the hypothalamus?

A

Within the hypothalamus there are a series of GnRH neurons that produce and secrete GnRH into the hypothalamic-hypophyseal circulation

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15
Q

How does GnRH move along the HPG axis?

A

GnRH crosses the primary plexus first and moves to the secondary capillary complex where it comes into contact with the gonadotroph cells in the anterior pituitary

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16
Q

What is the effects of GnRH binding to its receptor?

A

Once GnRh binds to the GnRH receptors in the anterior pituitary, LH and FSH can be synthesised

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17
Q

What is kisspeptin?

A

Kisspeptin is a G-protein coupled receptor ligand for GPR54

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18
Q

Where is kisspeptin expressed?

A

Hypothalamic expression - ARC and AVPV nuclei

Upstream of GnRH

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19
Q

What is the role of kisspeptin in HPG axis?

A

Kisspeptin neurons send projections to GnRH neurons, and bind to GPR54 / KISS1 receptor (kisspeptin receptor) expressed on GnRH neurons

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20
Q

Describe the structure of kisspeptin

A

Kisspeptin is expressed as a preproprotein that undergoes proteolytic cleavage into Kisspeptin-54 (Metastin as its a tumour suppressor)

Kisspeptin-54 undergoes further cleavage into kisspeptin 14, 13 & 10

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21
Q

Where is GnRH secreted form?

A

Synthesised and secreted from ~1000 GnRH neurons primarily in the arcuate nucleus

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22
Q

How is GnRH secreted in the hypothalamus?

A

Secreted in a pulsatile fashion - pulse generator orchestrated

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23
Q

What is the role of GnRH in the reproductive HPG Axis?

A

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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24
Q

Describe the structure of GnRH?

A

GnRH is also synthesised as a preproprotein and then cleaved into a simple decapeptide.
It’s also secreted along with a GnRH Associated Protein (GAP)

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25
Q

How often is GnRH secreted form the hypothalamus?

A

GnRH is secreted in pulses from hypothalamus every 30-120min

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26
Q

What does a GnRH pulse stimulate?

A

A GnRH pulse stimulates a pulse of LH and FSH secretion from the anterior pituitary
Pulsatile GnRH secretion is vital for stimulation of LH/FSH secretion

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27
Q

What effect does GnRH pulsatile frequency have on the HPG axis?

A

Slow frequency pulse favours FSH release, rapid pulse frequency favours LH
Continuous release results in cessation of response

28
Q

How do we exploit GnRH therapeutically?

A

take advantage of the pulsatile nature

29
Q

What is the structure of synthetic GnRH?

A

same structure as endogenous GnRH

30
Q

How is synthetic GnRH administered in patients?

A

pulsatile administration through a pump for a stimulatory effect

31
Q

Which patients are given synthetic GnRH?

A

Stimulatory for patients undergone pubertic delay or with GnRH mutations

32
Q

What are the therapeutic uses of GnRH?

A 
Synthetic GnRH
GnRH analogues (more common)
33
Q

What is the structure of GnRH analogues?

A

modified GnRH peptide structure

34
Q

What does single bolus dose mean?

A

A bolus is a single, large dose of medicine

35
Q

How are GnRH analogues administered?

A

Single bolus as it has a longer half life so binds to the receptor longer

36
Q

What is the advanatge of having a longer GnRH half life

A

Endogenous half life is ~2-4 mins

Alter GnRH analogues to extend half life - gives higher receptor affinity

37
Q

What are the effects of GnRH analogues?

A

loss of pulsatility

38
Q

What effect does a loss of pulsatility have on the HPG axis?

A

shuts down HPG axis (good as prevents production of hormones aiding proliferation of cancer and IVF stimulation protocols) 🡪 Inhibitory

39
Q

What is the function of GnRH agaonists?

A

GnRH agonists bind to GnRH receptor causing an initial flare of GnRH activity, increasing release of LH/FSH
HPG axis suits down shortly afterwards

40
Q

What are the effects of GnRH antagonists?

A

Bind to receptor and block the receptor ∴no activity

41
Q

Outline the normal GnRH response in the HPG axis

A
  1. Binding to GnRH receptors
  2. Activation of signalling (FSH & LH)
  3. Stimulation of gonadotrophin synthesis and secretion
  4. Dissociation of GnRH from GnRHR
  5. GnRHR responsive to next GnRH pulse
42
Q

Describe the step by step activity of a GnRH agonist in the HPG axis

A
  1. Binding to GnRH receptors
  2. Activation of signalling (FSH & LH)
  3. Stimulation of gonadotrophin synthesis and secretion
  4. Uncoupling of GnRHR from G protein signalling
  5. GnRHR non-responsive to GnRH
43
Q

Outline the effect on the step by step effect on HPG axis of a GnRH antagonist

A
  1. Binding to GnRH receptors
  2. Blockage of receptor
  3. No downstream effects
44
Q

What are the clinical areas GnRH is used?

A
  • Ovulation induction and IVF
  • Prostate cancer
  • ER+ breast cancer in pre-menopausal women
  • GnRHR/GnRH + ovarian and endometrial cancers
45
Q

How is GnRH therapeutics used in IVF and ovulation induction?

A

Very lucrative industry: 2 billion USD
Use GnRH and GnRH analogues to shutdown HPG axis so menstrual cycle can be manipulated without interference from the HPG axis
Patient initially given doses of GnRH analogues - shutting down HPG axis, uncoupling it from the gonads. Exogenous FSH then administered to stimulate follicle growth

46
Q

How is Prostate Cancer treated using GnRH therapeutics?

A

Androgen dependent - involves shutting down HPG axis to deal with cancers

47
Q

What are the newer hormone related pathologies treated using GnRH?

A

Endometriosis
PCOS
Uterine fibroids

48
Q

Outline the effects of GnRH at the pituitary

A
  1. Extra hypothalamic input
  2. Hypothalamic neurotransmitters activated
  3. GnRH neurons excited
  4. GnRH synthesised and released
  5. Extra pituitary input
  6. Increases gene transcription of α and β-subunits of LH
    and FSH
  7. Pulsatile release of FSH and LH
49
Q

Which subunits form the Gonadotrophin hormones?

A

LH FSH and hCG contain α-subunits and β-subunits dimerised together to form the hormones

50
Q

What are the heterodimeric gonadotrophin peptides composed of?

A

common α-subunit and hormone-specific β-subunit
The α-subunits are the same sequence in FSH, hCG and TSH produced via constitutive pathway
The unique properties are provided by specific β-subunits which is GnRH dependent

51
Q

What is the role of the N-linked carbohydrate side chains?

A

N-linked carbohydrate side chains required for biological function
Deglycosylating FSH/LH will cause them to cease to be active

52
Q

What are the functions of the heterodimeric subunits on their own?

A

Free subunits have no biological action: α-subunit and β-subunits have no function on their own - have to be dimersied together

53
Q

How is gonadotrophin hormone production regulated?

A

α-subunits are synthesized in excess with β-subunit limiting the hormone concentration as its GnRH dependent

54
Q

What causes the pulsatile release of FSH and LH?

A

Pulsatile secretion due to pulsatile GnRH release from the hypothalamus but pulsatile secretion not necessary for biological activity

55
Q

Describe the structure of gonadotrophins

A

α-subunit is the same and hormone-specific β-subunits have different lengths and sequences

The Y structures are the carbohydrate side chains important for biological activity

56
Q

What is glycosylation?

A

The enzymatic process to link saccharides together to form glycans

57
Q

What is the role of LH in the Testis?

A
  • stimulation of Leydig cell androgen synthesis and
    secretion
  • Leydig cells have LH receptors allowing LH binding to
    secrete androgens specifically testosterone
58
Q

What is LH?

A

Luteinising hormone

59
Q

What are the effects of LH in the ovaries?

A
  • theca cells are analogues to the leydig cells also
    enabling androgen synthesis and secretion via LH
    receptors
  • ovulation: LH surge due to oestrogen positive feedback
  • progesterone production of corpus luteum: remodelling
    of ovulated follicle into corpus luteum during the luteal
    phase
60
Q

Describe the effects of FSH in the testes

A

Regulation of Sertoli cell metabolism and spermatogenesis through FSH receptor binding

61
Q

What are the effects of FSH in the ovaries

A
  • follicular maturation: via granulosa cell oestrogen
    synthesis
  • (androgens) testosterone from theca cells cross over into
    the granulosa cells where they’re converted into
    oestrogens
62
Q

What are seminiferous tubules?

A

Seminiferous tubules are the site of germination, maturation, and transportation of sperm cells within the male testes

63
Q

Describe the structure of seminiferous tubules

A

Seminiferous tubules are made up of columnar Sertoli cells (FSH receptors) surrounded by spermatogenic cells on the epithelial interior and stem cells exteriorly

64
Q

Where are leydig cells located in the male gonads?

A

Interstitial spaces of Seminiferous tubules is where leydig cells are found (LH receptors)

65
Q

Where are theca cells located in the female gonadal system?

A

Theca cells line follicle and possess LH receptor secreting androgens

66
Q

Where are granulosa cells found in the female gonads?

A

Androgens cross into granulosa cells directly lining the egg

67
Q

What occurs in the granulosa cells?

A

Androgens converted into oestrogen via aromatase enzyme

Reproduction (Physiology 2) (12 decks)

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