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Physiology 2 > HPG Axis I > Flashcards

HPG Axis I Flashcards

1
Q

What are the 3 key organs of the HPG axis and how do they interlink?

A

The hypothalamus and pituitary secrete hormones to act on the gonads (testes/ ovaries) to coordinate reproduction/ production of fertilisable gametes

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2
Q

What are the requirements of reproduction?

A
  1. Correct process of sexual determination and differentiation to determine the genotypic and phenotypic sex of the baby
  2. Sexual maturation to have occurred during puberty
  3. Sufficient production and storage of egg and sperm cells with their correct number of chromosomes
  4. Transporting and meeting of egg and sperm (sexual intercourse)
  5. Correct fertilisation, implantation, embryonic and placental development
  6. Nurturing (eat/ drink/ psychologically) until the child can live an independent life
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3
Q

What does the placenta do?

A

Supports embryonic/ foetal development

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4
Q

How is the HPG axis controlled?

A

Through negative feedback from the peptide hormones of the hypothalamus/ pituitary and the steroid/ peptide hormones of the gonads

Release of hormones from hypothalamus causes release of hormones from pituitary which causes release of hormones from gonad

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5
Q

Where is the one time positive feedback occurs, not negative? What is this important for?

A

In ovulation, oestrogen does it

Important for menstrual cycle in females and fertility in males

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6
Q

What type of hormones do the hypothalamus, pituitary and gonad release? Give examples

A 
Hypothalamus
Releasing hormones (RHs)
Gonadotrophin Releasing Hormone (GnRH), (Kisspeptin)

Pituitary
Stimulating hormones (SHs)
Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)

Gonads
Steroid hormones
Oestradiol (E2), progesterone (P4) and testosterone (all produced by both males and females). Also inhibin and activin

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7
Q

Where do oestradiol, progesterone and testosterone function?

A

Oestradiol and progesterone in females and testosterone in males

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8
Q

What is the purpose of inhibin and activin

A

They are peptide hormones

Feedback to pituitary to regulate FSH production

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9
Q

What does GnRH specifically do?

A

Binds to receptors on the anterior pituitary, specialising those cells to release LH and FSH into circulation

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10
Q

What do LH and FSH do upon release into circulation?

A

Bind to their receptors in the gonads, which causes release of gonad hormones which also negative feedback on special sites in the hypothalamus and pituitary

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11
Q

What is the general purpose of the gonadal hormones in males and females?

A

Males - produce viable gametes

Females - growth and development

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12
Q

What is the hypothalamus made of?

A

Different nuclei and specialised neurons that secrete hormones to perform functions such as reproduction, thermogenesis, appetite etc.

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13
Q

What is the route of GnRH from the hypothalamus?

A

GnRH travels from primary plexus, through the hypophysial portal vessel (via the median eminence) to the anterior pituitary where it binds to it’s receptor on gonadotroph cells (GnRHRs)

This stimulates synthesis and secretion of gonadotrophin hormones, LH and FSH, from the gonadotroph cells of the anterior pituitary.

GnRH binding to it’s receptors increased transcription of alpha and beta subunits of FSH and LH.

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14
Q

What is kisspeptin known as?

A

The master controller of puberty

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15
Q

What is the KISS1 gene and where is it found?

A

The gene that encodes the kisspeptin, found upstream of the GnRH gene

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16
Q

What does Kisspeptin do and how does it do it?

A

Regulates GnRH synthesis and excretion

Kisspeptin neurons lie next to GnRH neurons and they send kisspeptins to their receptors on the GnRH neurons to act in a paracrine fashion to cause GnRH release

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17
Q

Which 2 nuclei in the hypothalamus express kisspeptin?

A

ARC and AVPV

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18
Q

What type of hormone is kisspeptin?

A

Peptide hormone

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19
Q

How many variants does kisspeptin have and why?

A

It has 4 possible variants, the result of proteolytic cleaving of a much larger structure (it’s prepro form)

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20
Q

Which kisspeptin variant can and cannot be used in human studies?

A

Kp-54 can as it crosses the blood brain barrier

Kp-10 cannot, but is cheaper to use since it is shorter in length

21
Q

What was kisspeptin originally discovered as?

A

Metastin - a tumour suppressor

22
Q

How are GnRH secreted from the hypothalamus and why?

A

In a pulsatile fashion

So secretion of LH and FSH from gonadotroph cells can be differentiated

23
Q

What coordinates the pulsatile fashion of secretion of GnRH and any changes in that?

A

The pulse generator - group of neurons found in potentially 2 areas of the hypothalamus

24
Q

Describe GnRH’s structure

A

Small peptide hormone of 10 a.a’s only.

Large prepro protein is spliced to form it

25
Q

What is GnRH co-secreted with?

A

GAP peptide (GnRH associated peptide) - unknown function

26
Q

How does the pulsatility of GnRH release vary in males and females?

A

In males it is a consistent pulse but in females it depends on the stage of the menstrual cycle

27
Q

What does a GnRH pulse stimulate? What do different pulse frequencies favour?

A

A FSH/ LH pulse. A slow pulse frequency favours FSH where as a fast pulse frequency favours LH

28
Q

What happens if GnRH is provided in a continuous fashion?

A

The HPG axis ceases/ shuts down (but this can be reawakened with pulsatile GnRH provision)

29
Q

Why is it important for GnRH secretion to be pulsatile?

A

Helps FSH/LH secretion to mimick the ovarian cycle (e.g. allows for LH surge and spike in oestradiol to result in an increase in progesterone, since corpus luteum has been remodelled to produce a lot of progesterone)

30
Q

What is synthetic GnRH produced in?

How is it similar to endogenous GnRH?

How does it help with pubertal disorders?

A

It is produced in cell culture

It has the same primary sequence/ structure as endogenous GnRH

Helps someone with a pubertal disorder (where they lack GnRH) to undergo normal puberty (stimulates HCG axis and fertility)

31
Q

What do GnRH analogues do?

What are their structure?

How does it act?

A

Shut down/ downregulate HCG axis

They have a modified GnRH peptide structure which makes it have a longer half life than endogenous GnRH

Antagonists sit on the GnRH receptor and block it to cause loss of pulsatility, agonists cause an initial flare of activity then downregulation

32
Q

How are GnRH analogues given?

A

As a single bolus

33
Q

SEE SLIDE 16

A

ALRIGHT

34
Q

What are the therapeutic/ clinical uses of GnRH analogues?

A

Induces ovulation in IVF

Kills off androgen supply in prostate cancer since it is androgen responsive (same for other hormone responsive cancers/ diseases such as endometriosis)

Used in uterine fibroids (fibroids are non-cancerous growths that develop in or around the womb (uterus))

Used in PCOS (Polycystic ovary syndrome is a set of symptoms due to elevated androgens in females)

Used in ER + breast cancer (type of breast cancer) in pre-menopausal women

Used in GnRHR/GnRH + ovarian and endometrial cancers

35
Q

What is hCG and it’s function?

A

A gonadotrophin hormone released by the developing embryo as it implants in pregnancy

It rescues the corpus luteum so that it continues to make progesterone in the first trimester of pregnancy

It does this by binding the LH receptor

36
Q

Describe the structure of gonadotrophin hormones (e.g. hCG, LH, FSH)

A
  1. Heterodimers - 2 polypeptide chains, common alpha subunit (to all glycoprotein hormones such as TSH) and hormone specific beta subunit (regulated and limited by GnRH production + made in different pathway to alpha subunit + undergo different glycosylations + are of different lengths)
  2. Have N-linked carbohydrate side chains - required for biological function; deglycosylating them acts as inhibition
37
Q

How do the proportions of alpha and beta subunits differ?

A

The alpha subunits are synthesized in excess to the beta subunits - free subunits have no biological action so this limits the hormone concentration

38
Q

Do the gonadotrphin hormones require GnRH in a pulsatile fashion?

A

No - in IVF you can give one big bolus of GnRH and that is enough to stimulate follicular genesis

39
Q

What is the function of LH in the testes and ovaries?

A

Stimulates Leydig cells to synthesize androgens (testosterone) in testes

Stimulates theca cells to synthesize androgens + coordinates ovulation since it’s midcycle surge helps expel the oocyte from the ovary to be fertilised + it remodels the ovarian follicle remnant left upon expulsion to form the corpus luteum

40
Q

What is the function of FSH in the testes and ovaries?

A

In the testes it regulates Sertoli cells to provide the correct env. for sperm maturation

In the ovaries it matures the ovarian follicles via granulosa cells within them. The granulosa cells mediate oestrogen synthesis.

41
Q

Where is sperm produced?

A

In the seminiferous tubules, present in the lobules of the testes

42
Q

What do the seminiferous tubules connect to?

A

The epididymis via the rete testes

43
Q

What cells are between the seminiferous tubules and lining the tubules?

A

Between the tubules are Leydig cells which express the LH receptor. Upon binding, LH causes the synthesis of testosterone

Lining the tubules are Sertoli cells which express FSH receptors and, when bound to, provide the correct environment for spermatogenesis

44
Q

What type of cells line the outside and inside of an ovarian follicle?

A

Outside the ovarian follicle are theca cells which express the LH receptor to stimulate androgen synthesis

Inside are the granulosa cells where the FSH receptor is expressed to mature the follicle and stimulate oestrogen synthesis

45
Q

How do androgens convert to oestrogens?

A

Androgens cross the basement membrane between the theca and granulosa cells. Granulosa cells contain aromatase which converts androgens to oestrogens

46
Q

What happens when oestrogen production has to be increased?

A

FSH increases
Increases transcription and translation of aromatase
More androgens convert to oestrogen

47
Q

What hormones does the corpus luteum produce?

A

Progesterone mainly, oestrogen too

48
Q

Overview of LH and FSH binding in males and females

A

Males: LH binds to receptor in Leydig cells to produce testosterone. FSH binds to its receptor in sertoli cells to maintain spermatogenesis and provide the correct environment for that. Hormones always feedback in negative fashion in male

Females: LH binds to its receptor on theca cells to stimulate androgen production; FSH binds to its receptor on granulosa cells to stimulate translation of aromatase which converts androgens to oestrogens. In the luteal phase (starting with the production of the corpus luteum) progesterone is produced which feeds back negatively (apart from oestrodiol which feeds back positively for ovulation)

Physiology 2 (10 decks)

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