Montemayor's review DSA

Question 1

Klinefelter Syndrome

Answer 1

XXY Seminiferous Tubule Dysgenesis

Most common genetic form of male hypogonadism (~1:500) (~250,000 men in the U.S.)

Most common symptoms:
Infertility
Gynecomastia

Question 2

What promotes the intrauterine development of his testes?

Answer 2

SRY gene (sex-determining region on Y chromosome)
SRY transcription factor (TDF: testis determining factor)

Question 3

what keeps female phenotype from developing?

Answer 3

Antimϋllerian hormone  Mϋllerian duct regression

Which cells produce Antimϋllerian hormone?
Sertoli Cells

Question 4

What is required for the development of seminal vesicles, ejaculatory duct, and vas deferens/epididymis?

Answer 4

Testosterone action is required for these Wolffian duct structures to develop

Question 5

Which cells in the testes produce testosterone?

Answer 5

Leydig cells

Question 6

Which hormone stimulates fetal Leydig cell production of testosterone during development prior to fetal pituitary secretion of luteinizing hormone (LH)?

Answer 6

hCG (human chorionic gonadotropin)

Important concept: hCG can be substituted for LH in clinical attempts to stimulate spermatogenesis in oligospermic men due to its increased availability. hCG is structurally most similar to LH and binds LH receptors.

Question 7

What is required for the development of the penis, scrotum and prostate?

Answer 7

DHT (Dihydrotestosterone)
DHT required for external male genitalia & prostate
DHT binds same androgen receptor as testosterone, with greater affinity

Question 8

What enzyme is required for the conversion of testosterone to DHT?

Answer 8

5α-reductase-2

Question 9

Summary: Male Sexual Differentiation

Answer 9

week
6-8- differentiation of testes (SRY transcription factor)

8- retention of wolffian ducts (testosterone) , regression of mullerian ducts (antimullerian hormone)

9-13- male-type external genitalia (DHT)

Question 10

What promotes development of gynecomastia?

Answer 10

Elevated estradiol levels and increased estradiol-to-testosterone ratio
Peripheral conversion of testosterone  estradiol

Question 11

Which enzyme converts androgen to estrogen?

Answer 11

CYP19-aromatase

Question 12

What hormone is considered to be responsible for the normal initiation of puberty?

Answer 12

Resurgence of pulsatile sleep-associated GnRH secretion from the hypothalamus during adolescence, along with increased gonadotrope sensitivity to GnRH.
(Initial increase during gestation, again within the first 2 years of life, and then low activity until puberty)

Question 13

Primary hypogonadism:

Answer 13

Gonadotropin levels are elevated

Androgen production is reduced

Question 14

major, normal actions of androgens

Answer 14

Androgenic:
Differentiation of male internal (T) and external genitalia (DHT) in fetus.
Growth, development of secondary sexual characteristics at puberty
Maintenance of reproductive tract & production of semen
Initiation and maintenance of spermatogenesis

Anabolic:
Stimulation of erythropoietin synthesis
Stimulation of sebaceous gland secretion
Control of protein anabolic effects (nitrogen retention)
Stimulation of linear body growth, bone growth and closure of the epiphyses
Promotion of ABP synthesis
Maintenance of secretions of sex glands
Regulation of behavioral effects, including libido

Question 15

In which form is the majority of circulating testosterone found?

Answer 15

SHBG (sex hormone-binding globulin) bound: 45-60%
Serum albumin bound: 38-55%
Free: 2-5%

Question 16

Which cells are the primary site for the production of testosterone in males?

Answer 16

Leydig cells of the testes

Question 17

What protein is responsible for maintaining testosterone concentration in the testes?

Answer 17

ABP (androgen-binding protein)

Question 18

Why is it important for testosterone to be concentrated within the testes?

Answer 18

Maintenance of adequate concentration within the testes is essential for the promotion of adequate spermatogenesis

Question 19

development of testosterone in leydig cells

Answer 19

Cholesterol
↓
Pregnenolone
↓
Progesterone
↓
Androstenedione
↓
Testosterone (T)
↓
T + ABP (seminiferous tuble)
T + SHBG (circulation)
Estradiol (CYP19-aromatase)
DHT (5α-reductase-2)

Question 20

What promotes LH and FSH secretion?

Answer 20

Pulsatile hypothalamic GnRH release stimulates anterior pituitary LH and FSH secretion

Question 21

Which cells are the target of LH in the testes?

Answer 21

Leydig cells

Question 22

Which cells are the target of FSH in the testes?

Answer 22

Sertoli cells

Question 23

GnRH Therapy for Prostate Cancer

Answer 23

Continuous and high doses suppresses gonadotropin secretion
Inhibition of GnRH receptor replenishment –> insufficient receptor availability
↓ LH/FSH levels –> ↓ T

Question 24

What are some of the key functions of normal Sertoli cells?

Answer 24

Supportive Function:  
  * Maintaining blood-testis barrier
 Phagocytosis
 Transfer of nutrients to sperm 
 * Receptors for hormones & paracrines

Exocrine Function:
Fluid produced for sperm mobilization
Production of ABP * (Androgen binding protein)
Spermination: release of sperm from seminiferous tubule

Endocrine Function:
Expression of testosterone, ABP and FSH receptors
Production of AMH *(Antimϋllerian hormone)
CYP19 Aromatase: testosterone –> estradiol-17β (local)
Production of inhibin B to regulate FSH levels

Question 25

our Klinefelter patient has low serum testosterone levels and elevated gonadotropin levels (LH and FSH). What is the explanation for elevated LH and FSH levels?

Answer 25

Reduction in androgen production results in decreased negative feedback on the hypothalamic-pituitary-testicular axis

Question 26

Feedback Regulation of the Hypothalamic-Pituitary-Testicular Axis in Males

Answer 26

This axis shows both the positive and negative feedback systems for the release of both LH and FSH and their action on specific cells to potentiate the release of testosterone (Leydig cells) and nursing cells that function to help mature and nurture sperm to maturity (Sertoli cells).

Question 27

Summary of GnRH story

Answer 27

Pulsatile GnRH release

FSH (and T) –> Sertoli Cells
LH –> Leydig Cells
Note: hCG is structurally similar to LH and can act to stimulate Leydig cells

Inhibin: Negative feedback on FSH production (Inhibin B in men)
T, DHT, and E: Negative feedback mainly on LH (also FSH)

Question 28

Which 3 key hormones have an important function to promote adequate spermatogenesis in the normal male?

Answer 28

Testosterone from Leydig cells
Sufficient testicular concentration of testosterone (ABP, androgen-binding protein; produced by Sertoli cells)
FSH & LH (necessary for Leydig and Sertoli function)

Question 29

Hormonal Factors in Spermatogenesis

Answer 29

Luteinizing hormone, (LH), secreted by anterior pituitary, stimulates the Leydig cells to secrete testosterone.

Testosterone, secreted by Leydig cells. Essential for growth and division of the testicular germinal cells, beginning of sperm formation.

Follicle-stimulating hormone, (FSH), also secreted by anterior pituitary, stimulates the Sertoli cells (nursing cells) to nurse and form sperm. Process of spermatogenesis.

Estradiol, formed from the testosterone by the Sertoli cells when they are stimulated by FSH. Role in spermatogenesis. [Mechanism not completely understood]

Growth hormone is necessary for controlling background metabolic functions of the testes. GH promotes early division of the sperm. Without it, as seen in pituitary dwarfs, spermatogenesis is severely deficient or absent resulting in infertility.

Question 30

What treatment might be suggested for our patient with Klinefelter Syndrome?

Answer 30

Androgen replacement therapy

Question 31

What would be the likely effect of administering exogenous testosterone to this patient with klinefelter?

Answer 31

Virilization of secondary male sexual traits

Question 32

Would exogenous testosterone likely improve fertility of this patient?

Answer 32

No
Seminiferous tubule tissue is likely destroyed and the cause of infertility
AND, in general:
2. Exogenous testosterone (T, DHT, and estradiol-17β) promotes negative feedback on gonadotropin secretion
↓ LH –> further ↓ T production by Leydig cells  ↓ testicular [T] –> ↓ spermatogenesis

Question 33

Factors to Consider with Hypogonadism

Answer 33

Normal spermatogenesis almost never occurs when steroidogenesis is defective
Defective spermatogenesis can still occur despite normal steroidogenesis

Primary testicular failure: removes negative feedback from the hypothalamic-pituitary axis  ↑ plasma gonadotropins
Hypothalamic and/or pituitary failure: generally result in decreased gondadotropin and steroid levels and reduced testicular size

Gonadal failure before puberty results in the absence of secondary sex characteristics (eunuchoidism)
Men with a postpubertal testicular failure retain masculine features but exhibit low sperm counts or reduced ability to produce functional sperm

Question 34

failure of the testes to descend impairs what aspect of reproductive function?

Answer 34

maturation of spermatogonia (maintain good temp for those swimmers)

Question 35

guy has decreased facial and axillary hair, decreased penile length, and hypogonadism. Deficiency of what androgen most directly explains his physical exam findings?

Answer 35

DHT- directly required for facial and axillary hair growth

Question 36

antibodies bind and neutralize FSH bioactivity. These immunized men would have what change in hormone levels?

Answer 36

decreased serum inhibin B levels.