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Physiology 2 > Hypothamalic/Pituitary/Gonadal Axis (repro) > Flashcards

Hypothamalic/Pituitary/Gonadal Axis (repro) Flashcards

1
Q

What is needed to reproduce

A
  • Correct process of sex determination (genotypic sex) and sex differentiation (phenotypic sex)
  • Sexual maturation (puberty)
  • Production and storage of sufficient supply of eggs and sperm
  • Correct number 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

HPG axis controls reproduction

A

Gonadal function is controlled via feedback by:

  • Hypothalamic and pituitary peptide hormones
  • Gonadal steroid and peptide hormones
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3
Q

HPG axis hormones

A

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
- Coordinate gonadal function (hypo-pit-gonad) is needed for viable gamete production (male), growth and development (both)

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4
Q

Hypothalamus to Pituitary

A

Hypothalamic-hypophyseal portal system (transport path of GnRH):

  • Hypothalamus
  • Neural input
  • Primary plexus
  • Hypophyseal portal vessel
  • Secondary capillary plexus
  • Anterior pituitary
  • Circulation
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5
Q

Hypothalamus: Kisspeptin

A
  • Role in reproduction recently discovered (2001) as a gatekeeper of puberty
  • Hypothalamic expression (ARC and AVPV)
  • Upstream of GnRH
  • Kisspeptin neurons send projections to GnRH neurons
  • Binding to GPR54 expressed on GnRH neurons
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6
Q

Hypothalamus: GnRH

A
  • Synthesised and secreted from GnRH neurons
  • Secreted in a pulsatile fashion-pulse generator orchestrated
  • Hypothalamic express (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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7
Q

Pulsatility of GnRH

A
  • GnRH is secreted in pulses from hypothalamus every 30-120 mins
  • A GnRH pulse stimulates a pulse of LSH 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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8
Q

Therapeutic application of GnRH

A

Synthetic GnRH:
- same structure as endogenous GnRH
- pulsatile administration leads to stimulatory
GnRH analogues:
- modified GnRH peptide structure
- single bolus, long half life, loss of pulsatility leads to inhibitory
- agonists or antagonists

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9
Q

Mechanisms of action of synthetic GnRH and GnRH analogues

A 
GnRH:
1) Binding to receptor 
2) Activation of signalling 
3) Stimulation of gonadotrophin synthesis and secretion 
4) Dissociation of GnRH and GnRHR
5) GnRHR responsive to next GnRH pulse 
Agonist:
1) Binding to receptor 
2) Activation of signalling 
3) Stimulation of gonadotrophin synthesis and secretion 
4) Uncoupling of GnRHR from G protein signalling 
5) GnRHR non-responsive to GnRH
Antagonsit:
1) Binding to receptor 
2) Blockage of receptor 
3) No downstream effects
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10
Q

Clinical uses of GnRH and GnRH analogues

A
  • Ovulation induction and IVF (2 billion USD)
  • GnRHR/GnRH and ovarian and endometrial cancers
  • Prostate cancer
  • ER and breast cancer in pre menopausal women
  • Endometriosis
  • PCOS
  • Uterine fibroids
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11
Q

Pituitary to Gonds

A
  • extra hypothalamic input
  • hypothalamic neurotransmitters to GnRH neurons
  • releases GnRH
  • GnRH and extra pituitary input causes increased gene transcription of alpha and beta subunits of LH and FSH
  • Causes pulsatile release of LH and FSH
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12
Q

Gonadotrophin hormones (LH, FSH and hCG)

A
  • Heterodimeric peptides (common alpha-subunit and hormone-specific beta-subunit)
  • N-linked carbohydrate side chains required for biological function
  • Free subunits have no biological action
  • alpha-subunits are synthesised in excess with beta-subunit, limiting the hormone concentration
  • Pulsatile secretion due to pulsatile GnRH release from the. hypothalamus but pulsatile secretion not necessary fro biological activity
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13
Q

Functions of gonadotrophins

A 
Luteinising hormone (LH)
Testis: 
- stimulation of Leydig cell androgen synthesis 
Ovary:
- theca cell androgen synthesis 
- ovulation 
- progesterone production of corpus luteum 
Follicle-stimulating hormone (FSH)
Testis: 
- regulation of Sertoli cell metabolism
Ovary:
- follicular maturation 
- granulose cell oestrogen synthesis
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14
Q

Male gonadal steroid production

A
  • Leydig cells: LHR expression leads to androgen testosterone production
  • Sertoli cells:
    FSHR leads to Sertoli cell metabolism and spermatogenesis
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15
Q

Female gonadal steroid production

A
  • Corpus luteum: LHR and FSHR leads to progesterone and oestrogen
  • Theca cells: LHR leads to androgens
  • Granulosa cells: FSHR leads to oestrogen (aromatase)
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16
Q

Gonadal steroid hornones

A 
Oestrogens:
- Oestradiol and oestrone 
- Folliculogenisis 
- positive feedback triggers ovulation 
Androgens:
- Androstenedione, testosterone and dihydrotestosterone 
- Spermatogenesis 
Progesterone:
- Prepares the uterus for implantation 
- Maintains conditions required for the early stages of pregnancy
17
Q

Female HPG axis summary

A
  • Hypothalamus releases GnRH to pituitary
  • Pituitary stimulates release of LH and FSH into ovary
  • Causes theca cell to produce androgens and granulosa cells to produce oestrogen (and progesterone)
18
Q

Male HPG axis summary

A
  • Hypothalamus releases GnRH to pituitary
  • Pituitary stimulates release of LH and FSH into testis
  • Causes leydig cells to produce testosterone and sertoli cells to produce oestrogen
19
Q

HPG axis summary

A
  • HPG axis controls reproductive function in both males and females
  • In response to Kisspeptin, GnRH neurons release pulsatile GnRH projections which go on to bind to GnRH receptors on gonadotroph cells of the anterior pituitary
  • Gonadotroph cells in turn synthesise and secrete FSH and LH
  • FSH and LH make their way through the blood circulation to bind to receptors located in the cellular compartments of testes and ovaries
  • Results in synthesis and secretion of sex steroids: oestrogen, progesterone and testosterone
  • Sex steroids actively coordinate reproductive function and regulate the HPG axis mainly via feedback (+ve and -ve)
20
Q

Glossary l

A
  • Gonadotrophin releasing hormone (GnRH): a hypothalamic decapeptide hormone, released in a pulsatile fashion that controls the synthesis and secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary.
  • Luteinsing hormone (LH): a heterodimeric gonadotrophin hormone, comprised of a common alpha glycoprotein hormone subunit and hormone specific beta subunit.
    LH is synthesised and secreted by the gonadotroph cells of the anterior pituitary. It is released into the portal circulation and binds to its receptor (LHR) on the theca cells of the ovary and Leydig cells of the testis. It is essential for androgen production, and progesterone production.
  • Follicle stimulating hormone (FSH): a heterodimeric gonadotrophin hormone, comprised of a common alpha glycoprotein hormone subunit and hormone specific beta subunit. FSH is synthesised and secreted by the gonadotroph cells of the anterior pituitary. It is released into the portal circulation and binds to its receptor (FSHR) on the granulosa cells of the ovary and Sertoli cells of the testis. It is essential for oestrogen production.
  • Steroid hormones: Derived from cholesterol, steroid hormones (androgens, oestrogens and progesterone) are produced by the theca and granulosa cells of the ovary and Leydig and Sertoli cells of the testes, by the actions of the gonadotrophin hormones.
21
Q

Glossary ll

A
  • Adrenarche: The first endocrine event of puberty. It is the result of cellular maturation of the adrenal gland, which results in the increase in DHEA/DHEAS production. This usually occurs approximately 6-8 years of age and is independently regulated from gonadarche.
  • Gonadarche: The second endocrine event of puberty. The ‘re-awakening;’ of the HPG axis, initially presenting as a nocturnal rise in GnRH (measured via LH), and results in the initiation of fertility.
  • Tanner Stages of Puberty: Five stage scale of puberty, originally developed by the paediatric endocrinologist, James Tanner. It describes the physical changes in breast development (females), hair development and external genitalia, with the first stage of puberty being breast budding in females, and an increase in testicular volume > 4ml in males.
  • Consonance: The completion of each stage of puberty in the correct order, as denoted by the Tanner Stages of Puberty, known as the ‘smooth ordered progression’. The time that individuals take to go through each stage may differ, but the order in which the stages are completed remains the same between individuals.

Physiology 2 (38 decks)

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