Male Reproduction

Question 1

Describe the HPG axis in relation to male reproduction:

Answer 1

1. The hypothalamus releases GnRH in a pulsatile manner into the hypophyseal portal blood system
2. The GnRH moves to the anterior pituitary where it stimulates the release of LH and FSH into the blood stream
3. LH acts on the Leydig cells to stimulate testosterone synthesis and FSH acts on the Sertoli cells to stimulate spermatogenesis and inhibin synthesis

Question 2

What are the sites of negative feedback in the HPG axis in the Male?

Answer 2

• The main site of negative feedback is the negative feedback from testosterone on the hypothalamus to reduce GnRH secretion
• Inhibin produced by Sertoli cells causes negative feedback at the level of the anterior pituitary to negatively regulate FSH secretion
• Estrogen produced also acts on the hypothalamus but may have a small role in inhibiting the anterior pituitary

Question 3

What is the effect of castration of FSH and LH levels?

Answer 3

• If castration occurs there is no longer Leydig and Sertoli cells synthesising testosterone and inhibin respectively
• The lack of inhibin production by Sertoli cells causes an immediate increase in FSH secretion as it directly acts on the anterior pituitary (there is a reduction in negative feedback)
• The lack of testosterone means less negative feedback at the level of the hypothalamus which causes greater secretion of GnRH and subsequently greater levels of LH secretion. This is a slightly slower response as it involves the hypothalamus, then the pituitary.

Question 4

Describe Primary and Secondary Failure of the HPG Axis in Males:

Answer 4

1. Primary Failure: Also called hypergonadotropic hypogonadism means the hypothalamus and anterior pituitary gland are functioning normally but there is an issue in the gonads resulting in a lack of testosterone production. This is characterised by increased gonadotropin (LH and FSH) levels.
2. Secondary Failure: Also called hypogonadotropic hypogonadism is due to the hypothalamus and/or pituitary secreting extremely low levels of GnRH and/or LH and FSH. This means the testes do not recieve adequate hormonal stimulation. This is characterised by very low levels of the gonadotropins (LH and FSH) and can be corrected with GnRH/gonadotropin treatment.

Question 5

Describe the path of the sperm through the male reproductive tract:

Answer 5

• Sperm are produced in the seminferous tubules
• Sperm move from the tubules into the mediastinum rete testes and are then forced into the head of the epididymis by the contraction of the smooth muscle in the tunica albuginea
• Within the epididymis the sperm mature and are stored in the tail of the epididymis
• During ejaculation sperm move from the epididymis into the Vas deferens where they mix with constituents of semen and are then ejaculated via the urethra

Question 6

Describe how testicular descent occurs during embyronic development:

Answer 6

• 3 months after fertilization the testes which are located inside the abdomen (behind the peritoneal cavity) begin to descend
• The testes are connected to the gubernaculum which directs the testes and epididymis through the inguinal canal into the scrotal sac
• The gubernaculum remains fixed but the foetus becomes larger meaning the testes and epididymic become pulled down
• The sac of the peritoneum that decends with the testes eventually fuses and gives the testes mobility within the scrotal sac

Question 7

Why has the scrotum evolved?

Answer 7

• The scrotum has evolved to allow for the temperature control of the testes, as spermatogenesis occurs optimally at 34 degrees (which is lower than body temperature)
• The testes have a specialised spermatic blood supply that undergoes countercurrent heat exchange to cool the blood entering the testes
• The cremaster muscle pulls the testes closer to the body when exposed to cold
• The dartos muscle also contracts to increase wrinkling of the scrotal skin to decrease surface and area and reduce heat loss
• This is very important as heat prevents spermatogenesis and increases cancer risk
• Animals that do not have descended testes have specialised adaptations to allow this

Question 8

What are the important cell types in the seminiferous tubules?

Answer 8

1. Sertoli Cells
2. Germ cells
3. Peritubular myeloid cells

Question 9

Describe the function of Sertoli cells:

Answer 9

• Sertoli cells (also called Nurse cells) create a supporting environment for spermatogenesis
• The population of Sertoli cells is established prior to puberty
• Sertoli cells extend branches which form tight junctions between them which thus creates the blood-testis barrier (so the basal and adluminal compartments are seperated)
• Sertoli cells are supported by FSH and testosterone which stimulate spermatogenesis via a number of mechanims including synthesis of ABP, glucose transport and lactate production etc.

Question 10

Describe the process of spermatogenesis:

Answer 10

1. In the basal compartment of the seminiferous tubules there are spermatogonia (germ cells)
2. Spermatogonia divide by mitosis to increase the pool of spermatogonia- Type B spermatogonia once divided by mitosis can move through tight junctions into the adluminal compartment where they become primary spermatocytes
3. Primary spermatocytes undergo the first meiotic division to become secondary spermatocytes
4. Secondary spermatocytes undergo the second meiotic division to become spermatids
5. Spermatids then undergo spermiogenesis to become spermatozoa

Question 11

Describe the Spermatogenic cycle:

Answer 11

• The spermatogenic cycle has 8 stages
• Each stage relates to a particular relationship of cells within the seminferous tubule
• It is during Stage 8 that the spermatids are released (associated with low levels of inhibin) and after this occurs the seminferous tubule moves back into Stage 1
• A piece of seminferous tubule can be taken and it will have different stages of the spermatogenic cycle along it (the spermatogenic wave)
• The average duration of spermatogenesis is men is 64 days and the seminferous epithelial cycle is 16 days

Question 12

Describe the process of spermiogenesis:

Answer 12

• The final stage of spermatogenesis
• Is sees the formation of spermatids into spermatozoa
• It involves 5 main stages:
  1. DNA compaction and nuclear shaping
  2. Formation of the acrosome
  3. Development and specialisation of the tail
  4. Loss of cytoplasm
  5. Formation of the residual body
• This creates spermatozoa that are fully formed but immotile and immature, which then mature and gain motility in the epididymis

Question 13

What are the components of Interstitial Tissue?

Answer 13

• Leydig Cells: responsible for steroidogenesis (production of testosterone and oestrogen)
• Blood vessels
• Lymphatics
• Connective tissue and macrophages

Question 14

How is testosterone synthesised in the Leydig Cells?

Answer 14

1. LH from the pituitary moves through the blood and binds to LH receptors on the surface of Leydig cells
2. Activation of the LH receptor activates a pathway which involves the synthesis of cAMP which stimulate the cells to start producing androgens
3. Cholesterol is used as a precursor- the binding of the LH stimulates the first cleavage event which converts cholesterol into pregenolone
4. Pregnenolone can then be converted to testosterone by 2 pathways:
5. 1. Pregnenolone -> 17-OH Pregnenolone -> DHEA-> Androstenediol ->(a ring oxidation) Testosterone
6. 2. Pregnenolone -> progesterone -> 17-OH progesterone -> Androstenedione -> Testosterone

Question 15

What are the 3 outcomes for testosterone synthesised in the Leydig cells?

Answer 15

1. Secreted into the blood to act in the body and produce secondary sex characteristics
2. The testosterone can act on receptors in the Sertoli cells where it is converted to 5a-dihydro-testosterone (more functional than testosterone)
3. The testosterone in the Leydig cells can also be converted with the enzyme aromatase into oestradiol which is secreted into the blood (this also occurs in the Sertoli cell where the oestradiol may move either to blood or lumen of the seminiferous tubule but this occurs to a lesser extent

Question 16

What is 5a-DHT?

Answer 16

• 5a-Dihydrotestosterone is the more potent form of testosterone (has a 3x greater effect when it binds to an androgen receptor)
• Testosterone is converted to 5a-DHT by 5a Reductase

Question 17

Where does the synthesis of estrogen occur in males?

Answer 17

• Estrogen is synthesised by the conversion of testosterone by aromatase into estradiol
• This mainly occurs in the Leydig cells but also occurs in the Sertoli cells to a lesser extent

Question 18

How does testosterone signal via the androgen receptor

Answer 18

• When testosterone enters a cell such as the epididymis it will be converted into 5a-DHT
• 5a-DHT then displaces the protein bound to the androgen receptor (HSP) as it has a much higher affinity
  3. Two DHT-receptor complexes will dimerise, phosphorylate and then translocate to the nucleus to act on genes to regulate transcription

Question 19

What are the Functions of the Epididymis?

Answer 19

• The head (caput) of the epididymis absorbs fluid from the sperm and concentrates them
• The epididymis (all) also secretes various specific proteins
• As sperm move from the head to the tail (cauda) of the epididymis through the corpus the sperm mature and gain high forward motility and an ability to interact with the surface of the egg
• The tail of the epididymis stores the sperm prior to ejaculation
• all functions of the epididymis require DHT

Question 20

What are the Function of the Male Accessory Sex Glands?

Answer 20

1. Prostate:
   - Produces prostatic fluid (30% of seminal fluid) which contains high levels of zinc
   - Requires DHT
2. Seminal Vesicles:
   - Produces seminal fluid (60%)
   - Requires DHT
3. Bulbourethral Glands:
   - Produces lubricating fluid prior to ejaculation
   - Requires DHT

Question 21

Describe the pattern of testosterone secretion?

Answer 21

• Testosterone is secreted in a pulsatile manner; with each spike in testosterone secretion preceeded by a spike in LH secretion

Question 22

Describe how the levels of testosterone change throughout life:

Answer 22

• Before birth there is a peak in testosterone
• After birth there is a peak in testosterone
• Throughout childhood levels of testosterone remain low
• During puberty there is a sudden increase in testosterone levels
• Testosterone levels remain high and static throughout adult hood
• In later adulthood (>50 years) testosterone levels decline, leading to an increase in LH levels but a blunting of LH pulsatility

Question 23

Describe the 4 Classes of Hormones:

Answer 23

1. Peptides
   - short chains of amino acids e.g. GnRH
2. Proteins/glycoproteins
   - long chains of amino acids e.g. LH and FSH
3. Steroids
   - Derived from cholesterol and with a 4 ring structure e.g. estrogen and progesterone
4. Amino acid derivatives
   - Amino acids with modified groups e.g. Noradrenaline

Question 24

Describe Classical and Non-Classical Hormone Signalling:

Answer 24

1. Classical nuclear receptor signalling:
   - The most common form of signalling pathway sex hormones use
   - The effects mediated by this pathway take a considerable amount of time to become apparent
2. Steroid hormone moves through the cell membrane and binds to the nuclear receptor by displacing the heat shock protein
3. The steroid hormone and nuclear receptor complex will dimerise with another steroid hormone and nuclear receptor dimer
4. The dimer then moves through a nuclear pore into the nucleus
5. There the dimer interacts with transcription factors, coactivators and RNA polymeraises to alter gene transcription
6. Non-classical nuclear receptor signalling:
   - Less common
   - Causes a much more rapid effect than classical signalling
7. The steroid hormone binds to the receptor which is locked within/localised to the cell membrane
8. The binding of the hormone to the cell surface receptor causes the activation of many intracellular kinases which exert rapid effects

Question 25

How does Estradiol Treatment Affect the Prostate?

Answer 25

• Treatment with estradiol reduces testosterone production making the prostate smaller in size
• Treatment with estradiol also causes changes in the pathology of the prostate making it more likely to be tumorigenic

Question 26

Describe the Effect of:

1. A lack of ERa signalling in the testes
2. An overstimulation of ERa in the prostate

Answer 26

1. A lack of ERa signalling in the testes
   - The testes will develop normally in utero however there will be significant effects on testis function
   - Leads to fluid reabsorption in the efferent ducts causing swelling of the rete testis and dilution of sperm
   - Leads to atrophy of seminiferous epithelium
   - Disrupted sperm function
2. An overstimulation of ERa in the prostate: CAN PROMOTE ABBARENT GROWTH
   - Causes proliferation and inflammation of cells
   - Can lead to squamous metaplasia of the epithelial cells

Question 27

Describe the Effect of:

1. A knockout for the ERB gene:
2. The action of ERB signalling in the prostate:

Answer 27

1. A knockout for the ERB gene:
   - Undergo normal development of testes with no defects in spermatogenesis that cause problems with fertility
2. The action of ERB signalling in the prostate: CONTROLS CELL GROWTH
   - Leads to apoptosis and decrease in proliferation
   - Therefore a lack of ERB signalling leads to prostate hyperplasia in adulthood

Question 28

Where are the different sex steroid receptors expressed prostate?

Answer 28

Androgen Receptor: expressed in epithelia and stroma
Estrogen Receptor a: expressed in stroma

Estrogen Receptor B: expressed in epithelia and stroma