REPRO: Hypothalamic/Pituitary/Gonadal Axis II

Question 1

Briefly, describe puberty.

Answer 1

the period of sexual maturation, during which a person becomes capable of reproducing

The gonads produce mature gametes:

• the testes make spermatozoa
• the ovaries develop oocytes

Question 2

What is puberty defined as clinically?

Answer 2

increased breast development in females (thelarche)
increased testicular volume in male

It’s the secondary characteristics that develop, as the primary ones are present from birth.

Question 3

What are the two endocrine events that occur during puberty?

Answer 3

1. ADRENARCHE (that leads to PUBARCHE)
   
   • growth of pubic and axillary hair
   • growth in height
2. GONADARCHE
   
   • LH leads to steroid synthesis and the development of secondary characteristics
   • FSH stimulates the growth of testes in males and steroid synthesis and follicular genesis in females

Question 4

Describe adrenarche.

Answer 4

-change in adrenal androgen secretion due to cellular remodelling of the adrenal.

• DHEA and DHEAS (dehydroepiandrosterone sulphate) cause the maturation of adrenal glands
• secreted from the zona reticularis of the adrenal cortex.
• gradual increase in their serum levels, starting from the age of 6-15, to a 20-fold increase peaking at 20-25 years of age. It declines thereafter.
• There are no known mechanisms for the trigger of adrenarche.

Question 5

What is the consequence of adrenarche?

Answer 5

PUBARCHE
It is the appearance of pubic/axillary hair resulting from adrenal androgen secretion.

It is associated with increased sebum production, which can cause acne. Infection and abnormal keratinisation can also cause acne.

growth in height

Question 6

Describe gonadarche.

Answer 6

reactivation of HPG axis

• at 16th gestational week, HPG axis is activated for sexual differentiation as it is required for male differentiation
• HPG axis deactivated after birth
• HPG axis reactivated during puberty (11 years)

GnRH secretion
It is the activation of gonadal steroid production, leading to the production of viable gametes and the ability to reproduce.

Question 7

What changes in the pattern of LH secretion occur during puberty?

Answer 7

During early to mid-puberty, there is a nocturnal rise of LH secretion, after which the rise normalised throughout the 24 hour period.

by observing changes in the pattern of LH secretion you can observe GnRH because it mimics GnRH secretion and is easier to obtain
-(GnRH secreted into the hypophyseal portal vein)

Question 8

When are the pregnancy scans?

At what pregnancy scan can the baby’s sex be revealed and why?

Answer 8

12-13 weeks
20 weeks

at the 20th week scan because activation of HPG axis which results in sexual differentiation is at 16th gestational week

Question 9

What stimulates the onset of puberty?

Answer 9

We do not know exactly what causes the onset of puberty.
It’s clear that it is a maturational event within the CNS.

• the inherent (genetic) maturation of 800-1000 GnRH synthesising neurones?
• environmental/genetic factors?
• body fat/nutrition?
• kisspeptin?

Question 10

What does nutrition and body fat have to do with puberty?

Answer 10

There is a known link between fat metabolism and reproduction (eg. there is metabolic dysfunction in PCOS, a reproductive hormone imbalance syndrome).

Also, in people with anorexia nervosa/ people who undergo physical training, it is found that they have:

• a reduced response to GnRH
• decreased gonadotropin levels
• amenorrhea
• ^ all is restored when they are nourished/ they stop exercise

Question 11

What do mutations in the KISS1R (kisspeptin receptor) cause?

Answer 11

Inactivating mutations of KISS1R lead to:

• hypogonadism
• failure to enter puberty
• hypogonadotropic hypogonadism

Activating mutations of KISS1R lead to:
- precocious puberty

Question 12

How can leptin and ghrelin mediate puberty regulation?

Answer 12

they feed into the hypothalamus and regulate kisspeptin, which in turn regulates the onset of puberty

Question 13

What is consonance?

Answer 13

the smooth ordered progression of changes through puberty.

• ORDER of pubertal changes is same in everyone
• AGE OF ONSET/PACE/DURATION of changes will vary

The average age of menarche onset (in the UK) is 12.5 years, decreased by 2 years over the last 100, and looks to be still decreasing.

Question 14

Describe the Tanner stages of puberty.

Answer 14

It is a scale of physical measurements of development.

There are 5 stages, and it looks at 3 parameters:

• Breast Development in females
• pubic and axillary hair growth
• Testicular Volume and Penile Length in males

Question 15

Describe the physical changes in girls during puberty.

Answer 15

• breasts enlarge (thelarche, the first outward sign of E2 activity)
• pubic/axillary hair
• uterus enlarges, cytology changes, secretions occur in response to E2
• uterine tubes
• vaginal changes
• cervical changes
• height (earlier in boys than girls)
• body shape (hips widen, etc.)
• HPG axis activation (increase in ovarian size and follicular growth
• menarche (not equated with the onset of fertility)
• fertility (during the first year, around 80% of the menstrual cycles are anovulatory, irregular cycles)

Question 16

Describe the physical changes in boys during puberty.

Answer 16

• external genitalia (increase in testicular volume, growth of penis, scrotum, scrotal skin changes)
• vas deferens (lumen increases)
• seminal vesicles and prostate
• facial/body hair
• pubic/axillary hair
• larynx (androgens cause the enlargements of the larynx, Adam’s apple [projection of thyroid cartilage], the voice deepens)
• height
• body shape
• onset of fertility (the testosterone from the Leydig cells stimulates meiosis and spermatogenesis in Sertoli cells)

Question 17

Describe the growth spurt during puberty.

Answer 17

It’s a complex interaction, involving:

• growth hormone
• oestrogen (boys and girls)

It occurs earlier in females.
There is a biphasic effect of oestrogen on epiphyseal growth:
- low oestrogen levels, causes linear growth and bone maturation
- high oestrogen levels, causes epiphyseal fusion

Question 18

What is a pilosebaceous unit?

Main types of pilosebaceous units

Answer 18

a structure consisting of:
>hair+hair follicle+arrector pili muscle+sebaceous gland

Sebaceous PSU
Vellus PSU

Question 19

Describe the effect of androgens on the differentiation of pilosebaceous units (PSUs).

Answer 19

Sebaceous PSU
-androgens increase sebum production. This can cause infection resulting in acne.

Vellus PSU
-androgens differentiate vellus PSUs into:
>terminal PSUs responsible for beard growth
>APO-PSU responsible for axillary and pubic hair

Question 20

What are some psychological changes that occur during puberty?

Answer 20

1. an increasing need for independence
2. an increasing sexual awareness/interest
3. development of a sexual personality

*later maturation is associated with better adjustment because psychological and sexual behaviours are occurring in sync. It reduces the chances of the disconnect between the physical and psychological changes.

Question 21

Define precocious sexual development.

Answer 21

It is the development of any secondary sexual characteristics before the age of 8 in girls and the ages of 9-10 in boys.

Precocious puberty is when pubertal changes (ie. the premature activation of the HPG axis) occur too early, but still in consonance

Question 22

What are the two ways in which the premature reawakening of the HPG axis can occur?

Answer 22

1. Gonadotrophin-dependent (or central) precocious puberty: maintain consonance
   
   • excess GnRH secretion - idiopathic or secondary
   • pituitary tumour causing excess gonadotrophin secretion
2. Gonadotrophin-independent precocious puberty: loss of consonance
   
   • testoxicosis - activating mutation of the LH receptor
   • sex steroid secreting tumour
     - exogenous steroids causing early gonadal maturation
     - McCune Albright Syndrome: activating mutation in GNAS1 gene encoding Gas subunit, causing hyperactivity and overproduction of the hormone

Question 23

How would McCune Albright cause precocious puberty?

Answer 23

McCune Albright Syndrome is a result of an α G-subunit activating mutation. This is the hyperactivity of this signalling pathway, thus it will over-produce the hormones that work by this pathway.

LH and FSH work through this pathway, so we would get their overproduction, leading to precocious puberty.

Question 24

Define pubertal delay.

What is a common cause of the pubertal delay?

Answer 24

It is the absence of secondary sexual maturation by 13 years of age in girls (or absence of menarche by 18 years), or 14 years in boys.

delayed HPG axis activation

Question 25

What are three ways in which the awakening of the HPG axis is delayed?

Answer 25

1. Constitutional pubertal delay
   
   • affecting growth and puberty
   • 10 times more common in boys
   • secondary to chronic illness (eg. 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 (can occur with normal karyotype, via viral infection eg. mumps)

Question 26

What are some chromosomal abnormalities that can cause gonadal dysgenesis?

Answer 26

• Klinefelter’s Syndrome (an extra X chromosome, XXY)
  would have male genitalia, but also wide hips, long arms and legs, and some breast development
• Turner’s Syndrome (missing an X chromosome, XO)
  are shorter than usual, have underdeveloped or ‘streak’ ovaries