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 - egg and sperm have to be transported and meet
- Fertilisation, implantation, embryonic and placental development
- Capable of “independent” life
2
Q
What controls gonadal function?
A
It is controlled via feedback by:
- Hypothalamic and pituitary peptide hormones
- Gonadal steroid (and peptide) hormones
- Only on one occasion there is positive feedback which is in females during ovulation.
3
Q
What does the hypothalamus release?
A
It releases Gonadotrophin releasing hormone (GnRH), (kisspeptin).
4
Q
What does the pituitary release?
A
Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH)
5
Q
What do the gonads releases?
A
Oestradiol (E2), Progesterone (P4), Testosterone (M), Inhibin and activin.
6
Q
What does the HPG axis coordinate?
A
To coordinate gonadal function for viable gamete production (male), growth and development (both).
7
Q
What does the hypothalamus contain?
A
It contains specialised neurons within the brain that secrete hormones. It is composed of various nuclei that not only coordinate reproduction but other functions as well such as spermatogenesis, regulation of appetite etc.
8
Q
When was the role of kisspeptin in reproduction discovered?
A
2001
9
Q
Where is kisspeptin expressed in the hypothalamus?
A
In the arcuate nucleus and the anteroventral periventricular nucleus
10
Q
What is kisspeptin upstream to?
A
GnRH
11
Q
Describe the stimulation of kisspeptin
A
Kisspeptin neurons send projections to GnRH neurons, binding to GPR54 expressed on GnRH neurons.
12
Q
Where is GnRH synthesised and secreted?
A
From GnRH neurons
13
Q
How is GnRH secreted?
A
In a pulsatile fashion-pulse generator orchestrated
14
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.
15
Q
What causes the synthesises of GnRH?
A
In response to kisspeptin
16
Q
What is the structure of kisspeptin?
A
10 amino acids long after cleavage
17
Q
What is the structure of GnRH?
A
10 amino acids long
18
Q
When is GnRH secreted from the hypothalamus (minutes)?
A
Every 30-120 mins
19
Q
What does the GnRH pulse stimulate?
A
It stimulates a pulse of LH and FSH secretion from the pituitary.
20
Q
What do slow and rapid pulse frequency of GnRH favour?
A
Slow - FSH release
Rapid - LH release
21
Q
What happens when there is continuous release of GnRH?
A
Results in cessation of response
22
Q
What are the therapeutic application of GnRH?
A
- Synthetic GnRH: same structure as endogenous GnRH -> pulsatile administration - stimulatory
- GnRH analogues: modified GnRH peptide structure
23
Q
What does an inhibitory GnRH analogue do?
A
It has a single bolus, long half-life, loss of pulsatility. They can be used as agonists or antagonists
24
Q
Describe the mechanism of action of a synthetic GnRH agonist
A
- Bind to receptor
- Activation of signalling
- Stimulation of gonadotrophin synthesis and secretion
- Uncoupling of GnRHR from G protein signalling
- GnRHR non-responsive to GnRH
25
Describe the mechanism of action of a normal GnRH signalling profile
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
26
Describe the mechanism of action of a GnRH antagonist
1. Bind to receptor
2. Blockage of receptor
3. No downstream effects
27
What are the clinical uses of GnRH and GnRH analogues?
- Ovulation induction and IVF
- ER+ brain cancer in pre-menopausal women
- GnRHR/GnRH+ ovarian and endometrial cancers
- Prostate cancer
- Endometriosis
- PCOS
- Uterine fibroids
28
What is the structure of gonadotrophins?
All have a common alpha subunit and the either LHbeta, FSHbeta, hCGbeta
29
Describe the gonadotrophin pulses of the follicular phase
Blood is drawn every 20 mins
- Shows an increase in LH when there is a decrease in FSH.
- When there is a increase in FSH, LH decreases
30
What are the most important hormones from the anterior pituitary?
LH, FSH and hCG
31
What is glycosylation?
It is the enzymatic process to link saccharides togther to form glycans.
32
Why is glycosylation important?
It is important for FSH and LH to require carbohydrates (CHOs) to be active. When first used to make synthetic FSH, it didn't work because it wasn't glycosylated.
33
What maintains the corpus luteum?
The beta-hCG from developing blastocyst
34
Why is the reason for the pulse unclear?
It is unclear as it is not needed for growth of follicle or spermatogenesis.
35
What is the function of LH in testis?
Stimulation of leydig cell androgen synthesis
36
What is the function of LH in the ovary?
Theca cell androgen synthesis
Ovulation
Progesterone production of corpus luteum
37
What is the function of FSH in the testis?
Regulation of Sertoli cell metabolism
38
What is the function of FSH in the ovary?
Follicular maturation
| Granulosa cell estrogen synthesis
39
What do the leydig cells do?
They express LHR to produce androgens such as testosterone
40
What do the sertoli cells do?
They express FSHR that is important for sertoli cell metabolism for spermatogenesis.
41
What do the theca cells do?
They have LHR which produces androgens
42
What do the granulosa cells do?
They have FSHR which produce oestrogens
43
What does the corpus luteum do?
LHR (and FSHR) -> progesterone (and oestrogens)
44
What happens during puberty?
In the gonads, they produce mature gametes:
- Testes -> spermatozoa
- Ovaries -> oocytes
Breast development in females, and increased testicular volume in males
Secondary characteristics develop (primary are present at birth)
Profound physiological and psychological changes
45
Define puberty
Transition from non-reproductive to reproductive state
46
What are the two endocrine events of puberty?
- Adrenarche
| - Gonadarche
47
What happens during adrenarche?
Adrenal androgens cause the growth of pubic hair, axillary hair
Growth in height
48
What happens during gonadarche?
LH -> causes steroid synthesis for secondary sex characteristics
FSH -> causes the growth of testis in males and steroid synthesis/folliculogenesis in females
49
What are the androgens excreted from the adrenal cortex of the adrenal gland?
Dehydro-epiandrosterone (DHEA)
| Dehydro-epiandrosterone sulphate (DHEAS)
50
What happens to the levels of adrenal androgens?
There is a gradual increase across 6 to 15 years. There is 20-fold increase peaking at 20-25 years then it declines thereafter.
51
What specific area of the adrenal cortex are adrenal androgens secreted?
Secreted from zona reticularis of adrenal cortex
52
What triggers adrenarche?
There is no known mechanism
53
What is pubarche?
Appearance of pubic/axillary hair resulting from adrenal androgen secretion
54
What is pubarche associated with and what can they cause?
- High sebum production = acne
| - Infection abnormal keratinization = acne
55
What happens if pubarche occurs before 8 years (girls) or 9 years (boys)?
Precocious
56
When does gonadarche occur?
Several years after adrenarche (typically about 11 years of age)
57
What happens during gonadarche?
- Reactivation of hypothalamic GnRH
| - Activation of gonadal steroid production -> production of viable gametes and ability to reproduce
58
What are GnRH neurones?
They are specialist hypothalamic centres that synthesise and secrete GnRH
59
When is the HPG axis activated?
It is activated at the 16th gestational week.
60
How is GnRH released in the foetus?
It is released pulsatile in the foetus until 1-2 years postnatally when it ceases.
61
When is the pulsatile secretion of GnRH reactivated?
At 11 years; GnRH neurones 'restrained' during postnatal period age 10 years or more.
62
What is thought to stimulate the onset of puberty?
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?
63
What is the link between nutrition and the HPG axis?
In anorexia nerovsa/intensive physical training:
- There is a reduced response to GnRH
- Decrease in gonadotrophin levels
- Amenorrhea
- Restored when nourished/exericse stopped
64
What is the Frisch et al body fat hypothesis?
Certain % fat:body weight is necessary for menarche (7%) and required (22%) to maintain female reproductive ability.
65
What happens if there is inactivating mutations of KISS1R or the gene coding kisspeptin?
It can cause hypogonadism, failure to enter puberty or hypogonadotrophic hypogonadism
66
What happens if there is a activating mutations of KISS1R?
Precocious puberty
67
What else does kisspeptin influence?
- Gonadal function
- Leptin (satiety) in the adipose tissue
- Ghrelin (hunger) in the gut
68
What is consonance?
It is "smooth ordered progression of changes".
69
What is the average age of menarche onset?
12.5 years
70
What is the age of onset, pace and duration of puberty in changes dependent on?
Wide inter-individual differences
71
Describe the tanner stages of puberty: scale of physical measures of development
1. Pubic and axillary hair growth
2. Testicular volume and penile length (male)
3. Breast development (female)
4 and 5. Mature Completion of puberty
72
What are the physical changes in girls during puberty?
- 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
73
What is thelarche?
First outward sign of E2 activity
74
What are the physical changes in boys during puberty?
- External genitalia
- Vas deferens
- Seminal vesicles and prostate
- Facial/body hair
- Pubic/axillary hair
- Layrnx
- Height
- Body shape
- Onset of fertility
75
What are the physical features in the larynx area of boys?
- Androgens -> enlarge layrnx, Adam's apple (projection of thyroid cartilage)
76
What is the peak height velocity of females and males?
```
Females = 9cm/year reached at 12 years
Males = 10.3cm/year reached at 14 years
```
77
What does testosterone do in physical changes in boys?
Testosterone from leydig cells stimulates meisosis and spermatogenesis in Sertoli cells
Boys are fertile at the beginning of puberty
78
What causes a growth spurt?
A complex interaction between growth hormone and oestrogen.
79
When does a growth spurt occur in girls?
It occurs earlier in girls approx. 2 years.
80
What is the biphasic effect of oestrogen on epiphyseal growth?
- Low levels cause linear growth and bone maturation
| - High levels cause epiphyseal fusion
81
What are the effects of androgens on the differentiation of pilosebaceous units (PSUs)?
- 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.
82
What are the psychological changes in puberty?
1. Increasing need for independence
2. Increasing sexual awareness/interest
3. Development of sexual personality -> later maturation = better adjustment
83
What is precocious sexual development?
Development of any secondary sexual characteristics before the age of 8 in girls and before the age of 9-10 in boys
84
What is gonadotrophin-dependent (or central) precocious puberty?
Consonance
- Excess GnRH secretion - idiopathic or secondary
- Excess gonadotrophin secretion - pituitary tumour
85
What is gonadotrophin-independent precocious puberty?
Loss of consonance -
- Testotoxicosis - activating mutation of LH receptor
- Sex steroid secreting tumour of exogenous steroids
86
What is the most common gonadotrophin-independent endocrine disorder?
McCune Albright Syndrome
87
What are the symptoms of the McCune Albright Syndrome?
- 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
88
What is pubertal delay?
Absence of secondary sexual maturation by 13 years in girls (or absence of menarche by 18 year) or 14 years in boys
89
What is delayed HPG Axis activation?
1. Constitutional delay
2. Hypogonadotrophic hypogonadism (low LH and FSH)
3. Hypergonadotrophic hypogonadism (high LH and FSH)
90
What happens in constitutional delay?
- 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
91
What are some types of hypogonadotrophic hypogonadism?
- Kallman's syndrome (X-linked KAL1 gene, Impaired GnRH migration)
- Other mutations causing defects in GnRH production
92
What are some types of hypergonadotrophic hypogonadism?
- Gonadal dysgenesis and low sex steroid levels:
| - Gonadal dysgenesis with normal karyotype, viral e.g. Mumps
93
Give some examples of gonadal dysgenesis
- Kinefelter's syndrome XXY or variants
| - Turner's syndrome XO
94
What are two classic symptoms of turners?
- Being shorter than normal
| - Underdeveloped or "streak" ovaries
