Physiology Block 3 Week 16 14 Male Reproductive Endocrine

Question 1

How is male sex determined and formed?

Answer 1

Genetic sex determined at conception

Y chromosome develops testis

Testes produce:

• testosterone
• Mullerian Inhibiting Factor

Testosterone

• -stimulates wolffian ducts
• -converted to DHT–> makes male genitalia

Mullerian Inhibiting Factor
–stimulates Mullertian Duct Regression

Question 2

Male Reproductive Function from conception to senescence

Answer 2

1. @Fertilization–Fetal testes secrete MIF and androgens that induces male phenotype fetal differentiation
   - -testicular activity (steroidogenesis) stimulated by LH and FSH
   - -burst of fetal testosterone necessary for clear phenotype
2. @6 months–burst in gonadotropins induces dimorphic changes in brain
3. @Puberty–pulsatile GnRH increases, leading to increased FSH and LH bursts
   - -stimulates sperm production and steroidogenesis
   - -androgen production stimulates secondary male sex characteristics
4. Male climacteric is subtle, but a decrease in testosterone has been documented in aging men

Question 3

Testicular Steroidogenesis

Answer 3

Testosterone –> DHT

Enzyme: 5-alpha reductase
–only expressed in target tissue (Prostate and scalp)

Major pathway:
Pregnenolone (+ P450scc) -->
17-OH-pregnenolone (+P450c17) -->
Dehydroepiandrosterone (+17-ketoreductase) -->
Androstenediol (+3HSD) -->
Testosterone (5-alpha-reductase) --> DHT

Question 4

What is the physiological advantage of activating testosterone to DHT in peripheral tissue?

What other hormone can testosterone be converted to in target tissue?

Answer 4

1. DHT is 5x more potent than testosterone

2. Estrogen (CYP19 = aromatase)

Question 5

Where are these hormones secreted?

Testosterone
DHT
Estrogen
DHEA

Answer 5

Testosterone–made mostly in testis

DHT–mostly produced in prostate and scalp

Estrogen–mostly through peripheral conversion in LIVER or ADIPOSE TISSUE (aromatase)

DHEA sulfate sulfate–weak androgen from adrenal gland

Question 6

Mechanism of Action of Testosterone

Answer 6

Testosterone dissociates SHBG (sex-hormone binding globulin) and binds ANDROGEN receptor
–activates nuclear transcription and translation that expresses 5-alpha-reductase

5-alpha-reductase (prostate–not all tissues) allows conversion to DHT and can bind androgen receptor

Local target tissue activation of hormones!

Question 7

Male Puberty

Answer 7

GnRH–pulsatile in men and women to stimulate FSH and LH pulses
–Prolactin inhibits FSH and LH

LH (pulsatile release due to GnRH) drives testosterone production in Leydig cell (similar to Theca cell in women)
FSH drives spermatogenesis in Sertoli cell (similar to Granulosa cell in women)

Testosterone (&DHT) stimulates:

• -Secondary Sex Characteristics
• -Spermatogenesis
• -Linear Growth
• -Growth Hormone

Growth Hormone:

• -stimulates growth spurt: growth plate closed by testosterone
• -spermatogenesis

Question 8

Interaction of steroidogenic Leydig and spermatogenic Sertoli Cells

Answer 8

Hypothalmus releases GnRH which positively stimulates anterior pituitary to release LH and FSH in pulses to act on the testis

Testis:
LH positively stimulates Leydig cells to produce Testosterone:
–systemic: stimulate androgenic effects, neg feedback on AP and hypothalamus

• -intra-testicular: Testosterone diffuses to the Sertoli cell and under FSH stimulation:
• —stimulates spermatogenesis
• —produces inhibin enzyme (inhibits FSH or GnRH release)
• —produces estrogen (aromatase)
• —produces Androgen Binding Protein (ABG) which holds onto testosterone to keep it in seminiferous tubules to bathe sperm

Question 9

What usually causes low testosterone?

What is the treatment?

Answer 9

Usually Hypogonadism–results in a less than normal sperm count

Tx:

• -testosterone: would get rid of the symptoms, but would not increase sperm count
• -hCG: has homology of LH and FSH, so binds to LH and FSH receptors on Leydig and Sertoli cells–stimulates Leydig cells to synthesize local testosterone

Question 10

Why are pregnant women forbidden from handling 5-alpha reductase inhibitor pills?

Answer 10

Prevents conversion of testosterone to DHT, which inhibits fetus from normal male development

Question 11

Compare and Contrast Male vs. Female Puberty

Answer 11

LH and FSH don’t go up the same in girls
–FSH first to stimulate follicles

In boys, LH and FSH go up the same

Peak velocity growth is later in males

Question 12

Low Testosterone 
Low Gonadotropins (LH and FSH)

Indicative of?

Tx?

Answer 12

Secondary Hypogonadism (Hypogonadotropic hypogonadism)

• -Low LH and FSH leads to decreased stimulation of testis to produce testosterone
• -testes may be normal, but are not receiving a normal signal from AP gland
• -estrogen secreting tumor?–causes a decreased FSH and LH secretion from AP

Testosterone would not be zero because if remove gonads, adrenal gland still makes a little testosterone

Give Testosterone
–will need too check bone age to see if long bones have closed

Question 13

Low T4
Low Free T4
High TSH

Indicative of?

Tx?

Answer 13

Primary Hypothyroidism

If was secondary (from a pituitary disease), TSH would not be increased

Thyroid is getting hyperplastic and big from TSH stimulation, but for some reason is not producing normal amount of TH

Give Thyroid Hormone

Question 14

How do you test for adrenal insufficiency?

Answer 14

Take a basal cortisol level and check levels again after ACTH stimulation test

If cortisol appropriately rises, then is not adrenal gland insufficient

Question 15

In a patient with hypogonadism, can you treat with gonadotropins?

Answer 15

Can treat with gonadotropins

• -stimulates Leydig to create testosterone and Sertoli cells to stimulate spermatogenesis
• -this is a peptide, so needs to be injected regularly and is expensive

If solely want normal androgen function and characteristic, treat with testosterone in topical steroidal form
–avoid giving by mouth because can be toxic to the liver