Male Hormones lecture

Question 1

A female w/out period has 46, XY karyotype.

Why would this phenotypic female lack a uterus, cervix, and fallopian tubes?

Answer 1

No müllerian structures

Regression of müllerian duct structures requires Antimüllerian hormone (AMH)

Question 2

Which cells secrete AMH in order to promote regression of the female müllerian structures?

Answer 2

Sertoli cells of the testes

Question 3

A female w/out period has 46, XY karyotype.

What promoted the development of testes in this patient?

Answer 3

SRY gene (sex-determining region on Y chromosome)
SRY transcription factor (TDF: testis determining factor)
This patient is 46,XY

Question 4

A female w/out period has 46, XY karyotype.

What normally promotes the development of male external genitalia, which is lacking in this patient?

Answer 4

DHT (Dihydrotestosterone)

Question 5

What enzyme is required for the conversion of testosterone –> DHT?

Answer 5

5α-reductase-2
Expressed in the male urogenital tract, genital skin, hair follicles, and liver
5α-reductase-2 deficiencies: ambiguous or feminized external genitalia
5α-reductase-2 inhibitors: treatment of benign prostatic hyperplasia and prostate cancer (DHT trophic effects inhibited)

5α-reductase-1
Expression at puberty, primarily in the skin. Contributes to sebaceous gland activity and acne associated with puberty
5α-reductase-1 inhibitors

Question 6

Which cells in the testes produce testosterone?

Answer 6

Leydig cells (steroidogenic cells)

Question 7

During intrauterine development, before fetal pituitary luteinizing hormone (LH) action is initiated, which hormone stimulates fetal Leydig cell production of testosterone?

Answer 7

hCG (Human Chorionic Gonadotropin)

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 8

A female w/out period has 46, XY karyotype.
If this patient’s testes are producing testosterone and there is no deficiency in 5α-reductase-2, why did a penis, scrotum and prostate fail to develop?

Answer 8

DHT required for external male genitalia & prostate
DHT binds same androgen receptor as testosterone, with greater affinity
This patient has defective/absent androgen receptors; target tissues do not respond to DHT/T

Androgen Insensitivity: X-linked recessive

Question 9

A female w/out period has 46, XY karyotype.

Why did this genetic male develop female external genitalia?

Answer 9

“Default” in the absence of DHT action

Outer vagina, Labia majora/minora, clitoris

Question 10

A female w/out period has 46, XY karyotype.

Do expect this patient to have seminal vesicles, ejaculatory ducts, and vas deferens/epididymis associated with the testes?

Answer 10

No, testosterone action required for these Wolffian duct structures to develop
Defective androgen receptors

Question 11

Male sexual differentiation (gestational age in weeks)

Answer 11

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

8- retention of wolffian ducts (testosterone), regression ofmuellerian ducts (antimuellerian hormone)

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

Question 12

A female w/out period has 46, XY karyotype.

Considering that this patient lacks ovaries for estrogen production, why does the patient exhibit normal breast development?

Answer 12

Peripheral conversion of testosterone –> estradiol

Question 13

Which enzyme converts androgens to estrogens?

Answer 13

CYP19-aromatase

Question 14

A female w/out period has 46, XY karyotype.

Why is there scant axillary and pubic hair? What is required for pubertal hair growth?

Answer 14

Androgen receptor insensitivity

DHT action is lacking

Question 15

What hormone is thought to be responsible in initiating puberty?

Answer 15

GnRH
Resurgence of pulsatile, sleep-associated GnRH secretion from the hypothalamus during adolescence
Initial increase during gestation, again within the first 2 years of life, and then inhibition of GnRH neurons by the CNS until puberty; lower hypothalamic and pituitary set-point
Increased pituitary gonadotrope sensitivity to GnRH

Question 16

Actions of androgens

Answer 16

Androgenic:
Fetal differentiation of male internal (T) and external genitalia (DHT)
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 17

2 key enzymes for conversion of testosterone in target tissues

Answer 17

aromatase (–> eastradiol)

5 alpha reductase (–> dihydrotestosterone)

Question 18

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

Answer 18

Leydig cells of the testes

Question 19

Circulating testosterone is found in which forms?

Answer 19

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

Question 20

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

Answer 20

ABP (androgen-binding protein)

Question 21

Why must T be concentrated in the testes?

Answer 21

Adequate concentration within the testes is essential for maintaining normal rate of spermatogenesis
100 : 1 (intra-testicular : circulating)

Question 22

Hypogonadotropic Hypogonadism

Answer 22

Hypogonadotropic hypogonadism
= Congenital (Kallman syndrome: decreased or absent GnRH secretion, anosmia), idiopathic or acquired
- Plasma LH, FSH, and testosterone levels are low
- Testes are immature and have no sperm

Hypogonadism: defects in spermatogenesis, steroidogenesis, or both
Endocrine factors responsible for ~50% of hypogonadal/infertility cases

Question 23

Factors to consider with hypogonadism

Answer 23

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 24

What promotes LH secretion?

Answer 24

Pulsatile hypothalamic GnRH release stimulates anterior pituitary LH and FSH secretion

Question 25

Which cells express LH receptors in the testes?

Answer 25

Leydig cells

Question 26

Which cells express FSH receptors in the testes?

Answer 26

Sertoli cells

Question 27

GnRH Therapy for Prostate Cancer

Answer 27

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

Question 28

What are some of the key functions of Sertoli cells?

Answer 28

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 29

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

Answer 29

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 30

Hormonal Factors in Spermatogenesis

Answer 30

Luteinizing hormone (LH): stimulates Leydig cells to secrete testosterone

Testosterone (T): essential for growth and division of testicular germinal cells, beginning of sperm formation

Follicle-stimulating hormone (FSH): stimulates the Sertoli cells which are essential for supporting spermatogenesis

Estradiol (T is converted by aromatase to E): ER expressed on sperm cells, some evidence for a role in optimizing spermatogenesis

Growth hormone (GH): necessary for controlling background metabolic functions of the testes. Promotes early division of sperm. (Pituitary dwarfs: spermatogenesis is severely deficient or absent –> infertility)

Question 31

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

Answer 31

Positive and Negative feedback systems for the release of LH and FSH and their action on cells which potentiate the release of testosterone (Leydig cells) and cells that function to help nurture sperm to maturity (Sertoli cells)

Question 32

A 16 y/o male with an absence of signs of puberty

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

Answer 32

Virilization of secondary male sexual traits

Question 33

A 16 y/o male with an absence of signs of puberty

Would exogenous testosterone likely promote fertility of this patient?

Answer 33

No. Testosterone (Androgens: T, DHT, and estradiol-17β) promotes negative feedback on LH secretion, which is already low

↓ LH –> ↓ T production by Leydig cells –> ↓ testicular [T] –> ↓ spermatogenesis