HPG Axis Flashcards

1
Q

What do we need to reproduce?

A
  • Correct process of sex determination and differentiation
  • Sexual maturation (puberty)
  • Production and storage of sufficient supply of eggs and sperm Correct number of chromosomes in egg and sperm
  • Actual sexual intercourse/ IVF
    • Fertilisation, implantation, embryonic and placental development
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What controls gonadal function?

A

It is controlled via feedback by:

  1. Hypothalamic and pituitary peptide hormones
  2. Gonadal steroid (and peptide) hormones

! Only on one occasion there is positive feedback which is in females during ovulation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What does the hypothalamus release?

A

It releases Gonadotrophin releasing hormone (GnRH), (kisspeptin).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What does the pituitary release?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What do the gonads releases?

A

Female: Oestradiol (E2), Progesterone (P4)

Male: Testosterone (M), Inhibin and activin.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Describe the release of hormones from the HPG axis.

A
  • Series of GnRH neurons will produce and secrete GnRH
  • GnRH will be secreted into the hypophyseal portal circulation (primary plexus to secondary capillary plexus)
  • GnRH will bind to GnRH receptors on gonadotroph cells in the anterior pituitary to produce FSH and LH
  • FSH and LH bind to FSH/LH receptors on the gonads

Gonads secrete oestrogen, progesterone and androgens which will feedback to anterior pituitary and hypothalamus through neg. feedback

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is kisspeptin upstream to?

What does it regulate?

How does it do this?

A

Kisspeptin is upstream to GnRH and regulates GnRH production

It does this because kisspeptin neurons will send projections to GnRH neurons and bind to KISS1R expressed on GnRH neurons

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Where is kisspeptin expressed in the hypothalamus?

A

In the arcuate nucleus and the anteroventral periventricular nucleus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is kisspeptin upstream to?

A

GnRH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the structure of kisspeptin?

A

Expressed as a prepro protein which is cleaved into different types of kisspeptin

The most common is kisspeptin 54 (metastin) and kisspeptin 10

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What does GnRH do?

A

It binds to the GnRH receptor on gonadotroph cells of the anterior pituitary to stimulate the synthesis and secretion of gonadotrophin hormones - LH and FSH.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the structure of GnRH?

A

10 amino acids long

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

When is GnRH secreted from the hypothalamus (minutes)?

A

Every 30-120 mins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What does the GnRH pulse stimulate?

A

It stimulates a pulse of LH and FSH secretion from the pituitary.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What do slow and rapid pulse frequency of GnRH favour?

A

Slow - FSH release Rapid - LH release

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What happens when there is continuous release of GnRH?

A

Results in cessation of response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

How is synthetic GnRH administered and what does it stimulate?

A
  • Synthetic GnRH: same structure as endogenous GnRH -> pulsatile administration - stimulatory effect of fertillity e.g ovulation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are GnRH analogues?

How are they administered?

What are they used for?

What two forms do they exist in?

A
  • Modified GnRH structure
  • Single bolus administration = loss of pulsabillity
  • Inhibition of HPG axis
  • Exists in two forms agonist and antagonist
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Describe the mechanism of action of a synthetic GnRH agonist

A
  1. Bind 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Describe the mechanism of action of a normal GnRH signalling profile

A
  1. Bind to Receptor 2. Activation of signalling 3. Stimulation of gonadotrophin secretion and secretion 4. Dissociation of GnRH from GnRHR 5. GnRHR responsive to next GnRH pulse
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Describe the mechanism of action of a GnRH antagonist

A
  1. Bind to receptor 2. Blockage of receptor 3. No downstream effects
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the clinical uses of GnRH and GnRH analogues?

A
  • Ovulation induction and IVF (shuts down menstrual cycle so it can be manipulated)
  • Prostate cancer
  • Endometriosis -
  • PCOS
  • Uterine fibroids
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is the structure of gonadotrophins?

A
  • Heterodimeric peptide
  • Common alpha subunit
  • Hormone specific beta subunit
    • LHbeta, FSHbeta, hCGbeta
  • N-linked carbohydrated side - required for biological function
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What are the most important hormones from the anterior pituitary?

A

LH, FSH and hCG

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What action do the free subunits have in gonadotrophic hormones?

A

The free subunits have no biological function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

How are the alpha and beta subunits synthesised of gonadotrophic hormones?

A

he alpha subunits are synthesised in excess with beta subunits limiting the hormone concentration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is the function of LH in ovulation?

A

Maintains progesterone production of the corpus luteum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Why is the beta subunit of gonadotrophins released in a limited fashion?

A

The beta subunit is secreted in a limited fashion because it is dependant on GnRH

  • A slow pulse of GnRH = transcription of FSH beta
  • A fast pulse of GnRH = transcription of LH beta
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What is the function of LH in testis?

A

Stimulation of leydig cell androgen synthesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is the function of LH in the ovary?

A

Theca cell androgen synthesis Ovulation Progesterone production of corpus luteum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What is the function of FSH in the testis?

A

Regulation of Sertoli cell metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What is the function of FSH in the ovary?

A

Follicular maturation Granulosa cell estrogen synthesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What do the leydig cells do?

A

They express LHR to produce androgens such as testosterone

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What do the sertoli cells do?

A

They express FSHR that is important for sertoli cell metabolism for spermatogenesis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What do the theca cells do?

A

They have LHR which produces androgens

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What do the granulosa cells do?

A

They have FSHR which produce oestrogens

37
Q

What does the corpus luteum do?

A

LHR (and FSHR) -> progesterone (and oestrogens)

38
Q

What is the clinical definition of puberty?

A

Clinical puberty is defined as breast development in females and increased testicular volume in males

39
Q

Define puberty

A

Transition from non-reproductive to reproductive state

40
Q

What are the two endocrine events of puberty?

A
  • Adrenarche - Gonadarche
41
Q

What happens during adrenarche?

A

Adrenal androgens cause the growth of pubic hair, axillary hair Growth in height

42
Q

What happens during gonadarche?

A

LH -> causes steroid synthesis for secondary sex characteristics FSH -> causes the growth of testis in males and steroid synthesis/folliculogenesis in females

43
Q

What are the androgens excreted from the adrenal cortex of the adrenal gland?

A

Dehydro-epiandrosterone (DHEA) Dehydro-epiandrosterone sulphate (DHEAS)

44
Q

What happens to the levels of adrenal androgens?

A

There is a gradual increase across 6 to 15 years. There is 20-fold increase peaking at 20-25 years then it declines thereafter.

45
Q

What specific area of the adrenal cortex are adrenal androgens secreted?

A

Secreted from zona reticularis of adrenal cortex

46
Q

What triggers adrenarche?

A

There is no known mechanism

47
Q

What is pubarche?

A

Appearance of pubic/axillary hair resulting from adrenal androgen secretion

48
Q

What is pubarche associated with and what can they cause?

A
  • High sebum production = acne - Infection abnormal keratinization = acne
49
Q

What happens if pubarche occurs before 8 years (girls) or 9 years (boys)?

A

Precocious

50
Q

When does gonadarche occur?

A

Several years after adrenarche (typically about 11 years of age)

51
Q

What happens during gonadarche?

A
  • Reactivation of hypothalamic GnRH - Activation of gonadal steroid production -> production of viable gametes and ability to reproduce
52
Q

What are GnRH neurones?

A

They are specialist hypothalamic centres that synthesise and secrete GnRH

53
Q

When is the HPG axis activated?

A

It is activated at the 16th gestational week.

54
Q

How is GnRH released in the foetus?

A

It is released pulsatile in the foetus until 1-2 years postnatally when it ceases.

55
Q

When is the pulsatile secretion of GnRH reactivated?

A

At 11 years; GnRH neurones ‘restrained’ during postnatal period age 10 years or more.

56
Q

What is thought to stimulate the onset of puberty?

A

It is clear that it is a maturational event within the CNS. - Inherent (genetic) maturation of 800-1000 GnRH synthesising neurones? - Environmental/genetic factors? - Body fat/nutrition? - Kisspeptin?

57
Q

What is the link between nutrition and the HPG axis?

A

In anorexia nerovsa/intensive physical training: - There is a reduced response to GnRH - Decrease in gonadotrophin levels - Amenorrhea - Restored when nourished/exericse stopped

58
Q

What is the Frisch et al body fat hypothesis?

A

Certain % fat:body weight is necessary for menarche (7%) and required (22%) to maintain female reproductive ability.

59
Q

What happens if there is inactivating mutations of KISS1R or the gene coding kisspeptin?

A

It can cause hypogonadism, failure to enter puberty or hypogonadotrophic hypogonadism

60
Q

What happens if there is a activating mutations of KISS1R?

A

Precocious puberty

61
Q

What else does kisspeptin influence?

A
  • Gonadal function - Leptin (satiety) in the adipose tissue - Ghrelin (hunger) in the gut
62
Q

What is consonance?

A

It is “smooth ordered progression of changes”.

63
Q

What is the average age of menarche onset?

A

12.5 years

64
Q

What is the age of onset, pace and duration of puberty in changes dependent on?

A

Wide inter-individual differences

65
Q

Describe the tanner stages of puberty: scale of physical measures of development

A
  1. Pubic and axillary hair growth 2. Testicular volume and penile length (male) 3. Breast development (female) 4 and 5. Mature Completion of puberty
66
Q

What are the physical changes in girls during puberty?

A
  • Breasts enlarge - Pubic/axillary hair - Uterus enlarges, cytology changes, secretions in response to E2 - Uterine tubes - Vagina - Cervical changes - Height - Body shape - HPG Axis - Menarche - Fertility
67
Q

What is thelarche?

A

First outward sign of E2 activity

68
Q

What are the physical changes in boys during puberty?

A
  • External genitalia - Vas deferens - Seminal vesicles and prostate - Facial/body hair - Pubic/axillary hair - Layrnx - Height - Body shape - Onset of fertility
69
Q

What are the physical features in the larynx area of boys?

A
  • Androgens -> enlarge layrnx, Adam’s apple (projection of thyroid cartilage)
70
Q

What is the peak height velocity of females and males?

A

Females = 9cm/year reached at 12 years Males = 10.3cm/year reached at 14 years

71
Q

What does testosterone do in physical changes in boys?

A

Testosterone from leydig cells stimulates meisosis and spermatogenesis in Sertoli cells Boys are fertile at the beginning of puberty

72
Q

What causes a growth spurt?

A

A complex interaction between growth hormone and oestrogen.

73
Q

When does a growth spurt occur in girls?

A

It occurs earlier in girls approx. 2 years.

74
Q

What is the biphasic effect of oestrogen on epiphyseal growth?

A
  • Low levels cause linear growth and bone maturation - High levels cause epiphyseal fusion
75
Q

What are the effects of androgens on the differentiation of pilosebaceous units (PSUs)?

A
  • Stimulate sebum secretion and together with infection this can cause acne. - Induce differentiation of vellus PSUs to terminal PSUs encouraging mustache and beard growth. - Induce differentiation of vellus hairs to apo-PSUs encouraging increased growth in areas of pubic and axillary hair.
76
Q

What are the psychological changes in puberty?

A
  1. Increasing need for independence 2. Increasing sexual awareness/interest 3. Development of sexual personality -> later maturation = better adjustment
77
Q

What is precocious sexual development?

A

Development of any secondary sexual characteristics before the age of 8 in girls and before the age of 9-10 in boys

78
Q

What is gonadotrophin-dependent (or central) precocious puberty?

A

Consonance - Excess GnRH secretion - idiopathic or secondary - Excess gonadotrophin secretion - pituitary tumour

79
Q

What is gonadotrophin-independent precocious puberty?

A

Loss of consonance - - Testotoxicosis - activating mutation of LH receptor - Sex steroid secreting tumour of exogenous steroids

80
Q

What is the most common gonadotrophin-independent endocrine disorder?

A

McCune Albright Syndrome

81
Q

What are the symptoms of the McCune Albright Syndrome?

A
  • Fibrous dysplasia - Cafe au lait skin pigmentation - Autonomous endocrine function: - most common gonadotrophin-independent precocious puberty - Hyperactivity of signalling pathways and over-production of hormones
82
Q

What is pubertal delay?

A

Absence of secondary sexual maturation by 13 years in girls (or absence of menarche by 18 year) or 14 years in boys

83
Q

What is delayed HPG Axis activation?

A
  1. Constitutional delay 2. Hypogonadotrophic hypogonadism (low LH and FSH) 3. Hypergonadotrophic hypogonadism (high LH and FSH)
84
Q

What happens in constitutional delay?

A
  • Affects both growth and puberty - Approx. 90% of all pubertal delay cases - About 10x more common in boys - Secondary to chronic illness e.g. diabetes, cystic fibrosis
85
Q

What are some types of hypogonadotrophic hypogonadism?

A
  • Kallman’s syndrome (X-linked KAL1 gene, Impaired GnRH migration) - Other mutations causing defects in GnRH production
86
Q

What are some types of hypergonadotrophic hypogonadism?

A
  • Gonadal dysgenesis and low sex steroid levels: - Gonadal dysgenesis with normal karyotype, viral e.g. Mumps
87
Q

Give some examples of gonadal dysgenesis

A
  • Kinefelter’s syndrome XXY or variants - Turner’s syndrome XO
88
Q

What are two classic symptoms of turners?

A
  • Being shorter than normal - Underdeveloped or “streak” ovaries