4/7 H-P Gonadal Circuit, Normal and Accelerated

Question 1

GnRH originally called what? why?

When GnRH is suppressed, is LH released? FSH?

Answer 1

Originally called LHRH, because in the adult (ie mature axis) it stimulates more LH than FSH release.

If GnRH is suppressed, FSH is released (due to constant basal level) but not LH.

Question 2

At what point in development is negative feedback evident? positive feedback?

Answer 2

Negative feedback present for both girls and boys in-utero.

Positive feedback present for girls later in pubertal development.

Question 3

What are the three stages of Maturation of the HPG circuit? aka “Maturational Changes of Negative Feedback”

Answer 3

1. Negative feedback first evident (in utero)
2. GnRH suppression (infant –> 8yrs old)
3. Desuppression (initial steps of puberty)

Question 4

What happens in males in utero when gonadotropins rise?

Answer 4

Testosterone is produced from testes, causes negative feedback –> gonadotropins drop

(Pink = gonadotropins; Red = testosterone)

Question 5

What happens in females in utero when gonadotropins rise?

Answer 5

Gonadotropins rise with testosterone then FSH levels drop due to feedback from placental sex steroids (estrogens)

(not entirely clear on this; asked question)

Question 6

If the first evidence of negative feedback in the HPG circuit occurs in utero for both girls and boys, what is the second evidence of negative feedback?

Answer 6

Remove maternal placental steroids at birth (white line): in female, the FSH levels rise (pink line).

Question 7

In male neonates, is there a postpartum drop in sex steroids?

Answer 7

No. Male neonate has fetal Leydig cells that persist for 6m postpartum (making testosterone) before declining. Purpose is to drive the descent of testes if needed.

Question 8

In the mid-childhood years, what happens to GnRH levels in both boys and girls?

blood levels of gonadotropins?

Answer 8

GnRH levels drop due to suppressors at the arcuate nucleus (GABA, dopamine, serotonin, melatonin)

Drop in GnRH -> drop in gonadotropins (LH/FSH)

-> blood levels of FSH =slight, levels of LH =very low

(blood FSH > LH)

Question 9

What blood levels of FSH and LH occur with the onset of puberty? why?

Answer 9

Initial step of puberty = desuppression of inhibitors in the arcuate nucleus

Now blood LH > FSH

Question 10

If you get blood levels of LH > FSH, you know that the cause is what?

Answer 10

When you get this blood result (LH>FSH), you know the origin is central (due to de-suppression of the arcuate nucleus) and due to pulsatile GnRH from the hypothalamus

Question 11

During what time of day does GnRH de-supression initially occur?

Answer 11

Initially occurs during sleep (in both boys and girls). [Does this explain wet dreams in little boys? ugh.]

Eventually becomes desuppressed both day and night.

Question 12

What are the requirements for positive feedback in the female? (3)

Answer 12

1. Follicular development with estradiol secretion
2. Blood level of estradiol at 250 pg/ml for 52 h
3. Adult pattern of pulsatile GnRH release

Question 13

Review: what cell does LH activate in the ovary? what cell does FSH activate? what does each cell type do?

Answer 13

LH –> Theca cell, cholesterol –> testosterone

FSH –> Granulosa cell, testosterone –> estradiol

Question 14

Describe the Hypothalamic-Pituitary Adrenal Circuit. Why is it relevant to repro?

Answer 14

Hypothal secretes Cortisol-Releasing Hormone to Anterior Pituitary;

Ant Pituitary releases POMC (breaks into ACTH/MSH)

ACTH –> adrenal glands to produce cortisol

Cortisol has negative feedback on Hypothal.

Relevance: Adrenarche occurs in mid-childhood. Responsible for appearance of pubic hair.

Question 15

Describe Adrenarche. what is it responsible for? what does it signify?

Answer 15

Rise of adrenal androgens in mid-childhood. (Gonadal androgens contribute later)

Responsible for pubarche (appearance of pubic hair)

First endocrine change of puberty.

Likely signifies the maturation of the zona reticularis (adrenal)

Question 16

Pubic hair: what causes its initial appearance? what secondarily contributes to its appearance?

Answer 16

Primarily from adrenal androgens

Secondarily from ovarian or testicular androgens

Question 17

If a child has neither breast nor pubic hair, what part of the circuit might be knocked out?

Answer 17

There may be a pituitary tumor (both HPA and HPG circuits knocked out)

OR a steroid enzyme defect (17-OH) causing inability to make androgens

Question 18

In the male, what does FSH do? LH?

Answer 18

Both act on components of the testis

FSH: stimulates seminiferous tubules, causes initial increase of testicular size at puberty.

LH stimulates Leydig cells. Causes 10x increase in testicular testostrone.

Question 19

Describe the Hypothalamic-Pituitary-Testicular Axis.

Answer 19

Two separate compartments within testis!

Spermatogenic Axis: GnRH -> pituitary -> FSH -> Seminiferous tubules -> inhibin (feedback to pituitary)

Androgenic Axis: GnRH -> pituitary -> LH -> Leydig cells -> testosterone (feedback to pituitary)

Question 20

Describe the Tanner stages of Thelarche (breast development) for females.

which ones would be most easily confused?

Answer 20

Tanner 1: no development

Tanner 2: hard nodule below areola

Tanner 3: breast expansion around areola

Tanner 4: areola stands out – double mound

Tanner 5: evens out with areola no longer standing out

(could confuse tanner 3 with 5 if looking at one moment in time)

Question 21

Describe the Tanner stages for males

Answer 21

(Male is less clear-cut than females)

Stage 1 - Preadolescent

Stage 2 - Enlargement of testes and scrotum (testes 2.7 cm/ 4 cc). Thinning and reddening of scrotum

Stage 3 - Enlargement of penis, mainly in length

Stage 4 - Further enlargement of penis in length and breadth; development of the glans

Stage 5 - Adult size and shape

Question 22

Summarize the Negative Feedback system.

Which two hormones are being referred to in this picture?

Answer 22

Summary

1. Present from intrauterine life;
2. Maturational changes after birth; and
3. First to mature at puberty.

Question 23

In the disturbing experiment with a monkey in which they caused a lesion to the arcuate nucleus to stop menstruation and then tried to figure out how to start it back up again, what did they learn about the GnRH pattern required for menses?

Answer 23

With a constant infusion of GnRH, menses did not resume

With pulsatile GnRH, menses were restored.

Reasoning: with constant infusion, there is downregulation/desensitization of the GnRH receptor

Question 24

Which hormone influences bone growth and allows the attainment of adult stature (both girls and boys)?

Answer 24

Estrogen

Question 25

What is the pattern of pubertal onset for Females? (based on British research after WWII....) - what is often the first sign of puberty? what age? - what usually happens next? - avg age of menarche? - at what point are 95% of cycles ovulatory?

Answer 25

1. **Thelarche (breast dev)** is often first sexual sign of puberty (ages 9 – 11) 2. **Growth spurt** after thelarche and pubarche 3. **Menarche (age 12.8 years) ** 4. ≤ 50% of cycles, 1st year ovulatory 5. **95% of cycles ovulatory 7 years later. **

Question 26

What is the pattern of pubertal onset for males (based on British after WWII)? ## Footnote - what is often the first sign of puberty? what age? - what usually happens next? - avg age of spermarche? (wtf is spermarche?)

Answer 26

1. Testicular enlargement (1st Sign of Puberty, ages 10 – 13.5) 2. Adrenarche (after age 10) 3. Penile and prostatic enlargement (average ages 11 – 14) 4. Accelerated growth 5. Spermarche (ability to reproduce), early (age 13.4) 6. Skeletal maturation (ages 10.5 – 16)

Question 27

What race of women reaches the onset of puberty earlier: whites or af-americans?

Answer 27

african americans. Puberty occurring earlier overall for both races, but 48% of af-ams reaching pubertal onset by age 8 compared to 5% of whites

Question 28

Describe the Tanner stages of Adrenarche (pubic hair) for females.

Answer 28

Tanner I: No pubic hair Tanner II: Scant pubic hair (you can count all of them) Tanner III: Diffuse pubic hair (a compulsive clinician can still count them) Tanner IV: Abundant hair limited to mons and labia (no one can count them) Tanner V: Adult pattern (extends onto thigh)

Question 29

What age defines precocious puberty in Af-Am girls? white girls?

Answer 29

Previous definition was pubertal onset prior to 8 yrs Now recommended to evaluate if breast dev or pubic hair before age 6 (Af-Am) or before age 7 (white)

Question 30

For girls, is delayed or precocious puberty more likely to be pathological? What about for boys?

Answer 30

**Girls: Delayed** is more likely to be pathological **Boys: Precocious** is more likely to be pathological

Question 31

Two main categories of precocious puberty? Which is typically gonadotropin dependent? independent?

Answer 31

- Central (aka complete): acting at the level of CNS. Usually gonadotropin dependent. - Peripheral (aka incomplete): appearance of one phase of puberty but not the others. Usually gonadotropin **in**dependent.

Question 32

Central/Complete precocious puberty: what occurs first? which is higher, LH or FSH? besides early physical development, what issues accompany central precocious puberty? what does it usually respond to?

Answer 32

- Initially, **early desuppresson of the arcuate nucleus** with GnRH secretion - **LH levels \> FSH** (expected after desuppression) - pubertal dev may be complete, including menses/ovulation, spermatogenesis, growth at epiphyseal plates - **Behavioral issues** common - **Should respond to GnRH agonists*** *which will downregulate the GnRH receptor

Question 33

What are the 3 main etiologies for Central/Complete precocious puberty?

Answer 33

- Idiopathic (majority) - Central causes: CNS lesion, hydrocephalus, vascular malformation - Girls: primary severe hypothyroidism

Question 34

What characterizes Incomplete/Peripheral precocious puberty in girls? boys?

Answer 34

_Girls:_ isolated thelarche (breast dev), isolated adrenarche (pubic hair), isolated menarche (very rare) _Boys:_ isolated sexual dev

Question 35

Four etiologies for precocious thelarche (aberrant ovarian estrogen production)?

Answer 35

- Isolated precocious thelarche (after birth, when GnRH levels are elevated; resolves at childhood with GnRH suppression) - McCune Albright Syndrome (triad of cafe-au-lait spots, bone dysplasia, GnRH independent precocity) - Autonomous estrogen-producing follicular cyst - Ovarian neoplasia making estrogen

Question 36

What is this a picture of? What syndrome is it classic for?

Answer 36

Cafe au lait spot McCune-Albright syndrome. Note maturing nipple and areola (triad of spots, gonadotropin-independent precocious puberty, bone dysplasia)

Question 37

Precocious Adrenarche in girls: 3 possible etiologies?

Answer 37

- Isolated precocious adrenarche (likely normal early pubarche of adrenal origin) -- WTF Jen is asking. - Congenital adrenal hyperplasia (usually 21-hydroxylase deficiency) - Insulin resistance (possible precursor to PCOS)

Question 38

What are a few possible etiologies for Peripheral Precocious Puberty in males? (rare condition)

Answer 38

- exogenous hormone - Gonadal tumor, androgen-producing - Adrenal tumor, androgen-producing - Adrenal hyperplasia (21-hydroxylas deficiency) - Leydig cell hyperplasia (activating LH receptor gene mutation)

Question 39

In infancy in girls, is FSH or LH usually higher? In what situations will isolated precocious thelarche occur?

Answer 39

In infancy, FSH is usually \>\> than LH Isolated precocious thelarche occurs in infants who have LH secretion (usually in infants there is **very little** LH secr)