Hypothalamic/Pituitary/Gonadal Axis II

Question 1

What is puberty and what does it entail?

Answer 1

Transition from non-reproductive to reproductive state
Gonads produce mature gametes:
- Testes  spermatozoa
- Ovaries  oocytes
Breast development in females, and increased testicular volume of above 4ml in males.
Secondary characteristics develop (primary are present at birth)
Profound physiological changes
Profound psychological changes

Question 2

What are the two endocrine events of puberty?

Answer 2

The first one is adrenarche, caused by the secretion of adrenal androgens
This is responsible for what we call pubarche; the growth of pubic and axillary hair as well as a growth in height
The second is gonadarche, which is caused by reactivation of the HPG axis causing the synthesis and secretion of LH and FSH

Question 3

What are the roles of LH and FSH in puberty?

Answer 3

LH and FSH are responsible for the synthesis of steroids leading to secondary sex characteristics
FSH is also responsible for the growth of testis in males and folliculogenesis in females
These events are independently regulated

Question 4

What happens during adrenarche?

Answer 4

Change in adrenal androgen secretion due to cellular remodelling of adrenal gland.
Dehydro-epiandrosterone (DHEA)*
Dehydro-epiandrosterone sulphate (DHEAS)
Look at the graph below:
- Gradual increase 6  15 years
- 20-fold increase peaking at ̴20-25 years
- Declines thereafter
- No change in other adrenal steroids
Secreted from zona reticularis of adrenal cortex
No known mechanism for trigger of adrenarche

Question 5

What happens during pubarche?

Answer 5

Appearance of pubic / axillary hair resulting from adrenal androgen secretion (DHEA and DHEAS)
Associated with:
- ↑ sebum production = acne
- Infection, abnormal keratinization = acne
If before 8 years (girls) or 9 years (boys)
= PRECOCIOUS puberty

Question 6

What happens during gonadarche?

Answer 6

Several years after adrenarche (typically ~11 yrs of age)
Reactivation of hypothalamic GnRH
Activation of gonadal steroid production  production of viable gametes and ability to reproduce

Question 7

What is GnRH and its function in gonadarche?

Answer 7

GnRH is synthesised & secreted by specialist hypothalamic centres – GnRH neurones.
HPG axis is first activated at 16th gestational week, so by week 20 you can tell the sex with a scan
- Pulsatile GnRH secretion in foetus until 1-2 years postnatally when ceases
- Re-activation at ~11 years
GnRH neurones ‘restrained’ during postnatal period  10 years or more
At puberty a gradual rise in pulsatile release of GnRH

Question 8

Why do we study GnRH levels by measuring LH?

Answer 8

Studying GnRH using LH because GnRH is only present in the hypophyseal circulation so there are ethical problems
Changes in the pattern of LH secretion occurring during pubertal development

Question 9

What stimulates the onset of puberty?

Answer 9

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

Question 10

How does nutrition and body fat affect puberty?

Answer 10

Link between fat metabolism & reproduction
Anorexia nervosa / intensive physical training
- Reduced response to GnRH
- ↓gonadotrophin levels
- Amenorrhea
- Restored when nourished / exercise stopped
Frisch et al.: body fat hypothesis
- Certain % fat:body weight necessary for menarche (17%) & required (22%) to maintain female reproductive ability

Question 11

How does kisspeptin affect puberty?

Answer 11

Inactivating mutations of KISS1R or the gene coding for kisspeptin:
	- Hypogonadism
	- Failure to enter puberty
	- Hypogonadotrophic hypogonadism
Activating mutations of KISS1R:
	- Precocious puberty

Question 12

What is consonance?

Answer 12

“Smooth ordered progression of changes”
Order of pubertal changes is uniform (but only that)
So the order of progression of pubertal changes is known as consonance
Age of onset, pace & duration of changes
Wide inter-individual differences
Average age of menarche onset (UK) = 12.5 years

Question 13

What is consonance based on?

Answer 13

Tanner stages of puberty: scale of physical measures of development
Based on:
1. Pubic and axillary hair growth (♀♂)
2. Testicular volume and penile length (♂)
3. Breast development (♀)
see charts for more detail

Question 14

What are the physical changes in girls during puberty?

Answer 14

Breasts enlarge
- thelarche – first outward sign of E2 activity
Pubic/axillary hair
Uterus enlarges, cytology changes, secretions in response to E2
Uterine tubes
Vagina
Cervical changes
Height
- earlier onset than boys
- peak height velocity (PHV) = 9 cm/y, reached at 12 yrs
Body shape
HPG axis
- increase in ovarian size and follicular growth
Menarche
- not equated with onset of fertility
Fertility
- in 1st year ~80% menstrual cycles anovulatory, irregular cycles

Question 15

What are the physical changes in boys during puberty?

Answer 15

External genitalia
- increase in testicular volume >4 ml
- growth of penis, scrotum, scrotal skin changes
Vas deferens
- lumen increases
Secretions from the seminal vesicles & prostate
Facial/body hair
Pubic / axillary hair
Larynx –
- androgens  enlarge larynx, Adams apple (projection of thyroid cartilage), voice deepens
Height
- PHV =10.3 cm/y reached at 14 yrs
Body shape
Onset of fertility
- testosterone from Leydig cells stimulates meiosis & spermatogenesis in Sertoli cells
- boys fertile at the beginning of puberty

Question 16

How does growth spurt occur during puberty?

Answer 16

Complex interaction
- Growth hormone
- Oestrogen (boys and girls)
Earlier in girls – approx. 2 years
Biphasic effect of oestrogen on epiphyseal growth
- Low levels -> linear growth & bone maturation
- Followed by high levels -> Responsible for epiphyseal fusion

Question 17

What is the effect of androgens on the differentiation of philosebaceous units (PSUs)?

Answer 17

The adrenal androgens (DHEA and DHEAS) act on the sebum pilosebaceous units, this results in the production of a lot more sebum causing the archetypal acne found in teens
With the vellus PSUs what happens is that, in response to the adrenal androgens there is a differentiation into the terminal PSU responsible for beard growth and the APO-PSU responsible for pubic and axillary hair growth

Question 18

What are the psychological changes that occur during puberty?

Answer 18

Increasing need for independence
Increasing sexual awareness/interest
Development of sexual personality
Later maturation = better adjustment
Precocious puberty happens without the psychological maturation to sync so this leads to psychological maturation later on

Question 19

What is precocious sexual development?

Answer 19

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

Question 20

How can precocious puberty occur?

Answer 20

Premature activation of HPG axis

1. Gonadotrophin-dependent (or central) precocious puberty – consonance because this is central activation
   
   • Excess GnRH secretion - idiopathic or secondary
   • Excess gonadotrophin secretion - pituitary tumour
2. Gonadotrophin-independent precocious puberty - loss of consonance
   
   • Testotoxicosis - here there is an activating mutation of LH receptor, meaning there are Leydig cells producing testosterone resulting in the enlargement of genitalia and secondary sex characteristics
   • Sex steroid secreting tumour or exogenous steroids

Question 21

What is McCune Albright syndrome?

Answer 21

Mutations in the GNAS1 gene so activation of widespread of G-protein signalling including GnRH secretion and LH and FSH synthesis and secretion
Café au lait skin pigmentation
Autonomous endocrine function – most common gonadotrophin- independent precocious puberty
Fibrous dysplasia
Hyperactivity of signalling pathways & over-production of hormones

Question 22

What is pubertal delay and what are the ways it can occur?

Answer 22

Absence of secondary sexual maturation by 13 years in girls (or absence of menarche by 18) or 14 years in boys
Characterised by a delayed HPG axis activation
1. Constitutional delay (a prolongation of the pre-pubertal phase):
affecting both growth and puberty. Approx. 90% of all pubertal delay cases.
~10X more common in boys
secondary to chronic illness e.g., diabetes, cystic fibrosis.

2. Hypogonadotrophic hypogonadism (low LH and FSH)
   Kallman’s syndrome (X-linked KAL1 gene, impaired GnRH migration),
   Other mutations causing defects in GnRH production
3. Hypergonadotrophic hypogonadism (high LH and FSH)
   Gonadal dysgenesis and low sex steroid levels:
   • gonadal dysgenesis with normal karyotype, viral e.g. mumps

Question 23

What is Klinefelter’s syndrome?

Answer 23

Klinefelter’s syndrome XXY or variants
Males with this karyotype have some feminine features including breasts and wide hips
Small testicular size
Affects 1 in 500 males
Gonadal dysgenesis resulting from abnormal karyotype

Question 24

What is Turner’s syndrome?

Answer 24

Turner’s syndrome XO
2 classic symptoms of Turners:
Being shorter than normal
Underdeveloped or “streak” ovaries
Affects 1 in 3000 females 
Gonadal dysgenesis resulting from abnormal karyotype