Lecture 15 - Endocrinology of Testis and Male Reproduction

Question 1

Is positive feedback involved in the male reproductive system? Why? What does this mean?

Answer 1

NOPE

High levels of testosterone in the male eliminates the possibility of positive feedback at the level of the median preoptic nucleus in the hypo

=> In the absence of testosterone, the default configuration is female!

Question 2

Describe the hormonal regulation of the male reproductive system.

Answer 2

1. GnRH stimulates LH release => LH reaches the testes and binds to LH receptors on
   Leydig cell => stimulates testosterone production in Leydig cells, and to a minor extent estradiol => testosterone then feedbacks negatively to the anterior pituitary to reduce sensitivity to GnRH + feedbacks negatively to the level of the hypothalamus, reducing GnRH release (high GABA/low glutamate)
2. GnRH stimulates FSH release => FSH reaches the testes and binds to FSH receptors on Sertoli cells in seminiferous tubules => in the presence of testosterone from the Leydig cells, the Sertoli cells will provide an environment for appropriate spermatogenesis => Sertoli cells produce inhibin => inhibin negatively feedbacks on the anterior pituitary to stop FSH release

Question 3

Does inhibin feedback to the level of the hypothalamus?

Answer 3

NOPE

Question 4

In what manner are LHRH and therefore LH and FSH secreted in the male? What to note?

Answer 4

Pulsatile circhoral rhythm every 1-2 hrs like in females

BUT FSH has lower baseline and peak values due to the inhibitory effects of inhibin

Question 5

Describe the Leydig cell LH receptor. How does it work?

Answer 5

GCPR

Adenylyl cyclease: ATP => cAMP => activates PKA => phosphorylates enzymatic systems => stimulation of conversion of cholesterol into testosterone production

Question 6

How does testosterone exit the Leydig cell?

Answer 6

Diffuses down its concentration gradient through the lipid bilayer because they are lipid based (just like all other steroid hormones)

Question 7

What happens to testosterone once it is released in the blood by Leydig cells? Consequence?

Answer 7

Bound by 2 plasma proteins:

1. Sex hormone binding globulin
2. Albumin

Inactive once bound

Question 8

Does testosterone decrease FSH levels?

Answer 8

NOPE

Question 9

Does inhibin decrease LH levels?

Answer 9

NOPE

Question 10

What determines whether testosterone or DHT will bind to the androgen receptor if both are present?

Answer 10

Whichever is present in higher concentrations

Question 11

Effect of estrogen secreted by Leydig cells?

Answer 11

Overwhelmed by testosterone effects, so none

Question 12

In what tissues is testosterone not converted to DHT?

Answer 12

Penis

Question 13

In what tissues can testosterone be converted to estrogen?

Answer 13

1. Brain
2. Hypo
3. Pituitary
4. Breast

Question 14

In what tissues is testosterone converted to DHT?

Answer 14

1. Hair follicles

2. Prostate

Question 15

What can testosterone be converted into at target tissues?

Answer 15

1. DHT

2. Estrogen

Question 16

What % of testosterone in blood is bound by plasma proteins?

Answer 16

97%

Question 17

How do steroid hormones induce their effects?

Answer 17

Bind to nuclear receptor complex which then binds to chromatin to impact transcription/translation

Question 18

Can testosterone bind plasma membrane receptors?

Answer 18

In some instances

Question 19

Describe the structure of inhibin. Where can it be produced? What to note?

Answer 19

2 subunits: alpha and beta (2 types for each)

Can be produced in Sertoli cells, but also the subunits can be made in FSH producing cells => 2 beta subunits can come together to make activin => stimulates FSH release

Note: these subunits have nothing to do with glycoproteins secreted by the pituitary

Question 20

Differences between inhibin and activin?

Answer 20

1. Inhibin: blood-borne and inhibits FSH release

2. Activin: not blood-borned (LOCAL) and stimulates FSH release

Question 21

Major actions of testosterone?

Answer 21

FETAL DEVELOPMENT OF:

1. Epididymis
2. Vas deferens
3. Seminal vesicles

PUBERTAL GROWTH OF:

4. Penis
5. Seminal vesicles
6. Musculature
7. Skeleton
8. Larynx

SPERMATOGENESIS

Question 22

Major actions of DHT?

Answer 22

FETAL DEVELOPMENT OF:

1. Penis
2. Penile urethra
3. Scrotum
4. Prostate

PUBERTAL GROWTH OF:

5. Scrotum
6. Prostate
7. Sexual hair
8. Sebaceous glands

PROSTATIC SECRETION

Question 23

How does testosterone promote the growth of the skeleton at puberty?

Answer 23

1. Stimulates GH secretion
2. Stimulates proliferation of bone cells
3. Stimulates closure of epiphyseal end plates of bones to terminate growth at the end of puberty

Question 24

How does testosterone promote the growth of the larynx at puberty?

Answer 24

Anabolic effects causing thickening of the vocal chords

Question 25

How do drugs against prostate enlargement or cancer work?

Answer 25

Block DHT by either:

1. Inhibiting 5-alpha reductase
2. Androgen receptor blocker

Question 26

Describe the changes in testosterone levels over the lifetime of a male.

Answer 26

1. 3 month of fetal development: peak due to hCG (analog of LH) and the early temporary activation of the hypo to produce LHRH and therefore LH => organizes the future male brain to eliminate the default positive feedback loop that is found in females
2. Peak shortly before, after, or during birth: hypothalamus becomes temporarily activated, driving testosterone production => essential in ensuring testicle descent
3. Very low levels from birth to puberty due to exquisite sensitivity of low levels of testosterone inhibiting LHRH/LH secretion by the hypo-pit unit
4. At puberty increased glutamate/decreased GABA in hypo + nocturnal LH levels rise => induce gonadotropic cells in the median preoptic nucleus to release LHRH, which then causes more LH to be produced => increased production of testosterone => by the end of puberty, a new, higher set point of testosterone is present = “resetting of the gonadostat”
5. Around age 60: decreased sensitivity of pituitary to LHRH stimulation, BUT enough to drive spermatogenesis (until about 90)

Question 27

What are variations in the height and slope of the 3 month fetal testosterone peak associated with?

Answer 27

Associated with variations in gender identity and sexuality

Question 28

Kallman syndrome: 8 symptoms?

Answer 28

1. Diminished muscle mass around shoulders
2. Fat deposition around hips
3. Scant pubic hair
4. Small penis and scrotum
5. “Milk-toast” personality (shy, lacking self-confidence, etc.)
6. ANOSMIA (inability to smell, key differential for this disease)
7. Overall under-virilized
8. Infertility

Question 29

Kallman syndrome: cause? Note?

Answer 29

Failure of migration of LHRH/GnRH neurons during fetal development from the olfactory bulbs where they are formed, due to many reasons such as genetic or diseased tissue in bulb or issues with proteins necessary to the migration

Note: this is why it is accompanied by anosmia!

Note: can also be partial

Question 30

Kallman syndrome: treatment? What to note?

Answer 30

Testosterone to restore secondary sex characteristics:

1. Get rid of fat deposits because testosterone is a lipolytic hormone
2. Enlarge muscle mass
3. Growth of pubic hair
4. Lengthening of penis and enlargement of scrotum

Note: treatment not able to restore fertility because still lacks FSH

Question 31

What is Kallman syndrome an example of?

Answer 31

Subset of conditions called hypogonadotropic hypogonadism

Question 32

Symptoms of precocious puberty in males? What to note?

Answer 32

1. Tall
2. Overdeveloped genitals
3. Increased sexual behavior

Note: cause and treatment are the same as for females