S4: Puberty and its Disorders

Question 1

What is puberty?

Answer 1

Puberty is the transition from non-reproductive to reproductive state and is where secondary sexual characteristics develop. These are characteristics we associate mature males and females with.
- The HPG axis, before the onset of puberty, is in a quiescent state waiting for re-activation.

Question 2

What are primary sexual characteristics?

Answer 2

They are what is present at birth and what we use to assign gender to.

Question 3

What are the two major endocrine events of puberty?

Answer 3

1. Adrenarche occurs first. It is the awakening of the adrenal due to maturation of adrenal cortex cells (reticularis). There is also secretion of adrenal androgens. The androgens results in growth of pubic and axillary hair (puberache) and growth spurt.
2. Gonadarche occurs next. This is the reawakening of the HPG axis and there is increased LH/FSH secretion and synthesis which activate gonadal function. Increased LH stimulates steroid synthesis which results in secondary sexual characteristics. Increased FSH causes growth of testis in the male, steroid synthesis and folliculogenesis in the female.
   - The two endocrine events are independently regulated, especially adrenarche we are still unsure of how it starts.

Question 4

Describe Adrenarche

Answer 4

• Adrenarche is a change (increase) in adrenal androgen secretion. Androgens are secreted from the new layer that has been developed, the zona reticularis of the adrenal cortex (remodelled from childhood). The zona reticularis isn’t really apparent in the neonate and only starts to develop as an independent zone as adrenarche occurs.
  ~Secretion~:
• The adrenal androgens that increase here in the adrenarche refers to the DHEA (dehydro-epiandrosterone) and DHEAS (dehydro-epiandrosterone sulfate) only. They are secreted from the zona reticularis and there is no change in other adrenal androgens.
• DHEAS enters the circulation and is transported to target tissues where it can be converted to testosterone or DHT.
• Adrenarche occurs from around the age 6 onwards and there is a gradual increase in DHEA and DHEAS levels from 6015 years. The elevation peaks at about 20-25 years. After this peak there is a decline in DHEA and DHEAS called the adrenopause.
  ~CAUSES~: There is no molecular trigger of adrenarche. It is thought to be leptin or insulin possibly related to body mass.

Question 5

What is pubarche?

Answer 5

Pubarche is induced by adrenarche (due to increased DHEA/DHEAS). It is characterised by the appearance of pubic and axillary hair. Pubarche is also associated with increased sebum production and infection and abnormal keratinization, both leading to acne.
- Pubarche occuring before age 8/9, it is precocious puberty.

Question 6

What are pilosebaceous units (PSU)?

Answer 6

• Consist of hair, hair follicle, arrector pili muscles and sebaceous gland.
• PSU deposit sebum on hair and bring it to the skin surface along the hair shaft.
• There are two different types of PSU: Sebaceous PSU (sebum) and Vellus PSU (fine).

Question 7

How do androgens affect vellus PSU?

Answer 7

Androgens will cause vellus PSY to differentiate into:
- Terminal PSUs that form the beard and moustache.
- APO-PSUs which form the public and axillary hair. These are sebasceous and apocrine part.
Also, increases in secretion from sebaceous glands due to androgens, abnormal keratinization or infection can cause infection.
These are androgen dependent events.

Question 8

Describe Gonadarche

Answer 8

Gonadarche occurs several years after adrenarche (typically around 11 years of age). There is reactivation of the HPG axis, reactivation of hypothalamic GnRH and therefore gonadotrophins.
This activates gonadal steroid production, which in turn leads to the production of viable gametes and the ability to reproduce.
- The HPG axis is actually first activated at the 16th gestational week, with pulsatile GnRH secretion in foetus. There is supression near term in foetus because maternal oestrogen and progesterone high –> negative feedback. It is reactivated in the neonate occurring 1-2 years postnatally until it eventually is supressed again till puberty. Then there is the reactivation of HPG axis at 11yrs in gonadarche.
- Therefore the GnRH are restrained during this period between the postnatal secretion and the onset of gonadarche, so restrained for about 10 years or more.
Then at puberty there is a gradual rise in the pulsatile release of GnRH. Interestingly the increase in GnRH secretion begins nocturnally.
- LH is a good indicator of GnRH secretion because when we see a pulse of GnRH we get a pulse of LH. Therefore LH levels increase in puberty. We use LH because to get to GnRH we would have to cannulate the hypophyseal circulation.
- As puberty progresses, there is more consistent GnRH pulsatile release. In the adult, the pulse frequency occurs during the day.

Question 9

Are LH and FSH released in pulses?

Answer 9

LH and FSH released in pulses mimicking those of GnRH. However, this is not needed for function.

Question 10

Describe how a growth spurt occurs

Answer 10

The growth spurt occurs as a result of complex interaction between growth hormone and oestrogen (present in both boys and girls).
- Oestrogens have a biphasic effect on epiphyseal growth. Low levels of oestrogens seen in early puberty support linear bone growth and bone maturation. At later puberty is reached, high levels of oestrogen result in epiphyseal fusion, which sees a decrease in growth spurt and bone fusion.

Question 11

What is the difference in growth spurt between genders?

Answer 11

• Girls experience the growth spurt earlier than boys by about 2 years.
• Boys grow more as puberty occurs later and they have lower levels of oestrogen.

Question 12

What are epiphyses?

Answer 12

Epiphyses are the rounded ends of bones that initially form separately to long bones and gradually fuse to the main shaft of the bone as an individual ages.
- Oestrogen affects their growth.

Question 13

What stimulates the onset of puberty?

Answer 13

It is a maturational event within the CNS. There is also other factors that may affect it.

Question 14

Describe the factors that may affect puberty

Answer 14

~Inhernet (genetic)~:
- Maturation of the GnRH synthesising neurones.
- Enviromental/genetic factors.
- Transcription factors, different affinities etc.
~Body fat/ nutrition~:
- Anorexia nervosa or intense physical training delays puberty; They show reduced response to GnRH thus they have reduced gonadotrophin levels and this results in amenorrhoea (period stops) or delayed puberty. The woman has lost reproductive ability (this makes sense as, gonadotrophin -> gonadal steroids -> gamete production/maturation). When nourishment occurs or the excersize stops, periods start again.
- The body fat hypothesis, predicts the % body fat required for menarche (17%) and required to maintain female reproductive ability (22%). This theory has been proven true.
- Leptin.
- Gut hormones.
~Kisspeptin~:
- Kisspeptin is a neurohormone found in hypothalamic neurones and their receptors are expressed on dendrites of GnRH neurones. Therefore it directly regulates GnRH secretion.
- The newest theory states some mutations in Kisspeptin activate or inactivate puberty initiation.

Question 15

What does mutations of the GPR54 (kisspeptin receptor) or the gene coding for kisspeptin results in?

Answer 15

• Abnormal development of GnRH neurones leading to hypogonadism (small gonadal structures, small testis/ovaries).
• Failure to enter puberty.
• Hypothalamic hypogonadism.
• Activating mutations of the kisspeptin receptor lead to precocious puberty.
• Deactivating mutations of kisspeptin receptor leads to delayed puberty.
  Therefore kisspeptin is critical in the initiation of puberty and reproductive function.

Question 16

What is consonance in puberty?

Answer 16

• Refers to a smooth ordered progression of changes.
• Regardless how long each pubertal transition takes in any given individual, the order in the changes happen remains the same.
• When puberty happens before consonance order –> disorder.

Question 17

What signals the beginning of puberty in men and women?

Answer 17

• Average age of mernarche in the UK is 12.5yrs.
• In females puberty starts with breast bud formation.
• In males it is when testicular volume increases to above 4ml. Prader orchidometer is a scale of beads, each representing a volume. Once testicular size has increased above 4ml then puberty has started.

Question 18

What is Tanner staging?

Answer 18

The Tanner Stages of Puberty allow us to classify where an individual is in the pubertal process using physical measurements. There are five stages, one being hasn’t yet entered puberty, five being completed puberty.

Question 19

Describe the physical changes in girls during puberty

Answer 19

• Breasts enlarge called ‘thelarche’. This is the first outward sign of E2 (estradiol) activity.
• Growth of pubic/axillary hair.
• Uterus enlarges, myometrium responds to oestrogen so there are cytology changes of uterus and secretions in response to E2.
• Uterine tubes, vagina, cervical changes.
• Height increase (growth spurt). Peak height velocity (PHV, fastest rate of growth) is reached at 12 years of age.
• Changes in body shape such as widening of the hips.
• HPG axis activation results in increase in ovarian size and follicular growth.
• Menarche (the first menstrual period) is not equated with onset of fertility as for first year around 80% of cycles are unovulatory and the cycles are irregular. Late onto puberty at Tanner stage IV.

Question 20

Describe the physical changes in boys during puberty

Answer 20

• External genitalia where there is an increase in testicular volume to above 4 ml (diagnostic of puberty starting). There is a growth of penis, scrotum and scrotal skin changes.
• Vas deferens lumen diameter increases.
• Seminal vesicles and prostate mature.
• Growth of facial/body hair.
• Growth of pubic/axillary hair.
• Larynx changes due to androgens that cause enlargement. There is development of the ‘Adams apple’, a projection of the thyroid cartilage and voice deepens.
• Height where 10.3 cm/year reached at 14 years.
• Body shape changes such as broadening of shoulders.
• Onset of fertility where testosterone from leydig cells and FSH stimulates meiosis and spermatogenesis in sertoli cells. Boys are fertile from the beginning of puberty (unlike with females), as soon as the HPG axis awakens.

Question 21

Describe the psychological changes during puberty

Answer 21

1. Increasing need for independence.
2. Increasing sexual awareness/interest.
3. Development of sexual personality.
   Generally speaking, later maturation generally results in better adjustment through puberty.

Question 22

What is precocious sexual development?

Answer 22

This is the development of any secondary sexual characteristics before the age of 8 in girls and before the age of 9-10 in boys. Precocious puberty is when pubertal changes occur early and can be divided up into whether consonance maintained (so the order you would expect puberty to occur) or not.

Question 23

Describe central preococious puberty

Answer 23

This is gonadotrophin-dependent precocious puberty. This occurs in consonance due to reawakening of HPG axis. it is associated with accelerated linear growth for age, advanced bone ages and increased levels of FSH, LH, oestradiol and testosterone.

• Most commonly excess GnRH secretion of hypothalamus that is idiopathic or secondary.
• Another possible cause is excess gonadotrophin secretion from a pituitary tumour or an issue with receptors.
• Treatment includes case-by-case assessment depending on age, psychological benefits, patients/carers wishes and expectation. GnRH analogues to suppress puberty until 11-12 years of age if appropriate. Surgery, radio or chemotherapy.

Question 24

What is hypothalamic hamartoma? How is it related to central precocious puberty?

Answer 24

Hypothalamic hamartomas are found in 33% of patients with central precocious puberty. A hamartoma is mostly benign, focal malformation that resembles a neoplasm in the tissue of its origin. The aetiology of this relationship is unclear, but it is suspected in some cases to be due to a non-physiological secretion of GnRH.

Question 25

Describe peripheral precocious (pseudo) puberty

Answer 25

This is Gonadotrophin-independent precocious sexual development and there is a loss of consonance. It is associated with suppressed FSH or LH levels (because steroids feedback and maintain gonadotrophin levels) and increased oestrogen or testosterone.
It may be caused by:
- Testotoxicosis which is an activating mutation of LH receptor, causing early virilsation of external genitalia. No FSH increase (e.g. No spermatogenesis).
- McCune Albright Syndrome.
- A sex steroid secreting tumour or exogenous steroids resulting in secondary sexual characteristics.
- Congenital adrenal hyperplasia - androgen production by adrenal glands due to enzyme block.

Question 26

Describe McCune Albright Syndrome

Answer 26

• Syndrome occurs due to a constant activation of adenylyl cyclase (constitutive activation of Gs subunit), leading to hyperactivity of these signalling pathways (cAMP) and over production of hormone. This is due to activating mutations of alpha subunit of Gs subunit of GPCR (includes LH and hCG).
• Results in a café au lait skin pigmentation, along with other endocrine disorders such as fibrous dysplasia.
• Is the most common gonadotrophin independent precocious sexual development.

Question 27

What is pubertal delay?

Answer 27

Pubertal delay is the absence of secondary sexual maturation (characteristics) by 13yrs in girls (or absence of menarche by 18yrs) or 14yrs in boys.

Question 28

List some reasons for pubertal delay

Answer 28

• Constitutional delay.
• Hypogonadotrophin hypogonadism (low LH and FSH).
• Hypergonadotrophin hypogonadism (high LH and FSH).
• Turners (45 XO).
• Klinefelter (47 XXY).

Question 29

Describe constitutional delay as a cause of pubertal delay

Answer 29

• Affects both growth and puberty and makes up approximately 90% of pubertal delay cases and is about 10x more common in boys than girls. It is where reactivation of HPG axis just doesn’t occur.
• Often hereditary multiple genes.
• It could also be secondary to chronic illness like cystic fibrosis or diabetes.

Question 30

Describe Hypogonadotrophin hypogonadism (low LH and FSH) as a cause of pubertal delay

Answer 30

• This is low levels of gonadotrophin hormones, may be a result of a genetic mutation e.g. Kallman’s syndrome (an X-linked mutation in the KAL gene, it affects the migration of GnRH neurones)
• May be other genetic causes for example hypopituitarism or impaired gonadotrophins.
• High dose or long term use of opioid or steroid (glucocorticoid) medicines.

Question 31

Describe Hypergonadotrophin hypogonadism (high LH and FSH) as a cause of pubertal delay

Answer 31

• High levels of gonadotrophin hormones, the problem here is at the gonadal level. There is normal higher functioning of hypothalamus and pituitary but something is going wrong at the gonads (gonadal dysgenesis) causing low sex steroid levels. This is why there is high LH/FSH.
• Congenital examples include Klinefelter syndrome (47XXY) incidence of 1:500 males, Turners syndrome (45XO) incidence of 1:3000 girls.
• May also occur due to gonadal dysgenesis with a normal karyotype such as viral e.g. mumps.

Question 32

Two classic symptoms of Turners

Answer 32

1. Being shorter than normal

2. Having underdeveloped or ‘streak’ ovaries