Diaz-Thomas - Male Puberty

Question 1

What is puberty?

Answer 1

• Process of physical maturation manifested by an INC in growth rate and the appearance of 2^o sex characteristics

Question 2

What tools do you need to assess pubertal devo?

Answer 2

• Stadiometer: measure 3x, and take the average
• Orchidometer: tool to measure testicular volume; 4cc volume the earliest sign of pubertal devo in M
• Growth charts
• Bone age: before and after puberty (open and closed epiphyses); left hand
  1. Bone age of 17: completed about 99% of adult growth potential

Question 3

What factors are important in stadiometer technique?

Answer 3

• Bare feet, with heels together
• Heels, buttocks, shoulders against stadiometer
• Legs straight and knees extended
• Looking straight ahead
• Holding deep breath in

Question 4

How do we assess the genetic potential for growth?

Answer 4

• Mean parental height (MPH): average of parent heights
  1. M: (dad ht + mom + 13.2 or 5.07)/2
  2. F: (mom ht + dad - 13.2/5.07)/2
• 2 SD = +/-10cm (4in)

Question 5

What is height velocity? How does it change in growing men?

Answer 5

• Speed of growth, measured in cm/yr
• Normal ranges are age and sex dependent
• Peak of pubertal growth spurt (Tanner stage 4): 10-12cm/yr (up from 5 at age 10, and 8 at age 3)
  1. Growth slows b/t birth and growth spurt, which can happen as early as 9, and as late as 13 for boys
  2. Annualized height velocity

Question 6

What is this? Color significance?

Answer 6

• Prader orchidometer:
  1. Blue (1-3cc): pre-pubertal volume
  2. Yellow (4-20cc): pubertal volume

Question 7

How does the skeleton mature in puberty?

Answer 7

• Epiphyseal plates fuse
• By the time you have developed facial hair, your growth plates are closed for the most part

Question 8

What is the GnRH pulse generator? Contributing factors?

Answer 8

• Restraint mech suppresses puberty (gonadostat)
• # of factors play a role in suppression (propensity to be on, unless it is restrained):
  1. NPY, GABA, leptin (prolonged excess), TGF-alpha

Question 9

What is KAL-1?

Answer 9

• Responsible for migration of the olfactory bulb and GnRH receptor migration
• If there is a problem with this gene, patient may have Kallman’s syndrome
  1. Hypogonadotropic hyogonadism: delayed puberty
  2. No sense of smell

Question 10

What factors lead to INC GnRH release at puberty?

Answer 10

• GPR54 and kisspeptin have INC expression at the time of puberty -> maximal expression
  1. Ligand and receptor stimulate LH and FSH via GnRH activation
  2. GPR54 is sensitive to GnRH antagonists

Question 11

How do GnRH/LH pulsatility vary throughout life?

Answer 11

• GnRH:
  1. Prepubertal: a) minimal GnRH release, b) FSH, LH low, c) gonadal hormones low
  2. Pubertal: a) INC in pulsatile freq and amplitude of GnRH, b) INC in FSH, LH pulses, c) rise in gonadal hormones
• LH: minimal in pre-puberty, nocturnal rise, then much higher levels in puberty

Question 12

What are some broad factors that contribute to puberty onset? Most important?

Answer 12

• Nutrition
• Environmental chemicals
• Ethnicity
• Genetic factors (50-80%):
  1. GnRHR
  2. KAL-1
  3. FGFR-1
  4. GPR54
  5. LHX3

Question 13

What are some miscellaneous factors involved in pubertal control?

Answer 13

• Neurotransmitters: GABA receptor (INH HPG axis), glutamate (stimulates HPG axis)
• Changes in expression of tumor suppressor genes permissive: Oct-2, EAP-1, TTF-1
• Genes contiguous w/elastin affect pace of puberty: Williams syndrome (del of 7q11.23 = early onset with rapid pace)
• Differential routing of signals: INH tracts routed through post hypothalamus, and stimulatory routed through ant hypothalamic preoptic area
• Endocrine disruptors, i.e., GH-IGF (onset + tempo)
• Nutrition and minimum weight (body fat) correlate with initiation (Frisch’s hypothesis)

Question 14

How is leptin involved in pubertal control?

Answer 14

• Secreted by fat cells, and acts on hypothalamus:
  1. Reduces appetite
  2. Stimulates gonadotropin release
• Deficiency = obesity + gonadotropin deficiency
• Prolonged excess downregulates GnRH release, and can contribute to the relative hypogonadism of obesity

Question 15

What happens in normal sex maturation in the fetoplacental unit and ealry infant life?

Answer 15

• Fetus grows in estrogen-rich environment due to function of fetoplacental unit
• Free testosterone, DHEA-S, 17KS are high
• HPG axis transiently activated (MINI-PUBERTY) before CNS INH fully mature
  1. Maximal at 3-4 months of age, and regresses gradually over the first 2 years

Question 16

Describe the mini-puberty of infancy in males.

Answer 16

• Rapid testosterone rise to 400ng/dL 1st day of life
• T declines rapidly during 1st week to 20-50, then INC over the first 2 months post-natally
  1. Surge is gonadotropin mediated (FSH>LH)
  2. Penile length INC
• Levels decline to pre-pubertal levels by year 1
  1. Inhibin elevated at 3 mos to 1 yr, reflecting Sertoli cell mass determining adult sperm quantity
• Early patterning of hormone devo is important for later devo

Question 17

What is going on with sex hormones in normal childhood?

Answer 17

• Gonadostat is maximally suppressed: nadir is reached in mid-childhood (6 years)
• Incomplete suppression as bioactive LH/FSH are secreted at low levels
  1. RARE to see sexual development at these low levels

Question 18

What is going on with GnRH/LH in the normally developing pre-pubertal child?

Answer 18

• Earliest change is rise in DHEA-S from adrenals
• Change in amplitude, then freq of discharge from the GnRH pulse generator
  1. Sleep-related INC in LH
  2. 25-fold rise in LH over the course of pubertal development
• LH response more robust than FSH response to GnRH, and LH:FSH ratio INC on stimulation

Question 19

What is the Tanner scale for testicular enlargement?

Answer 19

• Stage 1 (prepubertal): testicular size <4cc in volume, and <2.5cm in longest dimension
• Stage 2: enlargement of scrotum/testes, scrotal skin reddens/thins (11.9 yrs), growth of testes to 4cc or greater in volume (2.5-3.2cm)
• Stage 3: enlargement of penis (length first; 13.2 yrs), further growth of testes (3.3-4cm)
• Stage 4: INC size of penis with growth in breadth and devo of glans, testes/scrotum larger (4.1-4.5cm), scrotal skin darker (14.3 yrs)
• Stage 5: adult genitalia (15.1 yrs), testes >4.5cm
• Dr. D-T said this staging tends to be quite subjective
• NOTE: gynecomastia can be a normal part of development (uni- or bilateral)

Question 20

What are the pubertal milestones for boys based on Tanner staging (excluding testicular/genital devo covered on another card)?

Answer 20

• Stage 1: villus pubic hair only, 5-6cm/yr growth, adrenarche
• Stage 2: sparse growth of lightly dark hair at base of penis (12.3 yrs), 5-6cm/yr growth, DEC in total body fat
• Stage 3: thicker, curlier hair spreads to mons pubis (13.9 yrs), 7-8cm/yr growth, gynecomastia (13.2 yrs), voice break (13.5), muscle mass INC
• Stage 4: adult type pubic hair, no spread to thigh (14.7), 10.0cm/yr growth (peak height velocity), axillary hair (14), voice change (14.1), acne (14.3)
• Stage 5: adult type w/spread to thighs, but not up linea alba (15.3), deceleration and cessation of growth at 17 yrs, facial hair (14.9), muscle mass continues to INC

Question 21

What is the rough timeline for male pubertal devo (image)?

Answer 21

Question 22

What signs might you see in a boy with adrenarchy at age 6? What might this mean?

Answer 22

• Premature adrenarche: hair and body odor before testicular development
  1. Can be accompanied by transient growth spurt
• If this boy has 4mm testes, he has pre-pubertal development, and he could have a tumor

Question 23

What is constitutional delay?

Answer 23

• Auto dom inheritance
• Boy >> girls (2x)
• Age of onset of puberty delayed by average of 2.5 years in girls and 3 years in boys
• Rule out chronic medical conditions as a cause for delay

Question 24

What is testotoxicosis?

Answer 24

• Mutation of LH receptor, so Leydig cells start making testosterone out of control (auto dom)
  1. Aromatase INH used to improve final height: taller and more muscular than their peers

Question 25

What might you do for a boy with slightly delayed bone age, and a displaced INC in height velocity?

Answer 25

• This is most likely constitutional delay
• Provide counseling and reassurance

Question 26

How does timing of puberty vary?

Answer 26

• Varies with sex, race, and weight
  1. Note the attached height variation by race
• Involves normal range encompassing >95% of US population of children
• Abnormalities can occur with timing, sequence, and pace

Question 27

What is adrenarche? Hormonal changes? Physical changes?

Answer 27

• Mid-childhood before puberty
• Change in adrenal response to ACTH
• HORMONES: rise in 17-hydroxypregnenolone and DHEA relative to cortisol
  1. DHEA-S >40ug/dL considered adrenarchal
  2. Devo of zona reticularis: 2BHSD2 low, but CYTB5 and SULT2A1 (encodes DHEAST) high
• PHYSICAL: transient growth spurt
  1. Axillary and pubic hair growth
  2. NO sexual devo occurs