1. WINDSOR UNIVERSITY SCHOOL OF MEDICINE
Male Reproduction
Dr.Vishal Surender.MD.

2. Male Reproductive Physiology
The major organ involved in maintaining male reproductive function is the testis. A normal functioning testicle is required for
1)the production of mature sperm
2)and the synthesis of the major male reproductive hormone testosterone.

3. Physiological functions of major components-
The Male Reproductive System
Physiological functions of major components-

4. Section of human testis.
Seminiferous epithelium
* Blood–Testis Barrier
* Spermatogenesis

5. Interaction between the Sertoli and Leydig cells.
The testes
The role of the male testes are to produce the hormone testosterone as well as to produce spermatozoa and prepare them ready for reproduction. The testis is made up of hundreds of seminiferous tubules (where spermatogenesis takes place) – within these tubules are found the Sertoli cells. Leydig cells are found in the interstitial fluid surrounding the seminiferous tubules. The Sertoli and Leydig cells have important roles with regards spermatogenesis.
Function of the Sertoli cell
The Sertoli cell maintains close contact with developing sperm and provides structural support and nutrition. They phagocytose residual bodies/damaged germ cells, secrete fluids, assist in sperm detachment into lumen and synthesize transferrin (important for sperm development). An important function is the production of Androgen-binding protein that maintains high levels of androgens in the tubules and carries testosterone to the epididymus.
Diagram showing the interaction between the Sertoli and Leydig cells. Remember that the Leydig cell is in the interstitial fluid while the Sertoli cell is found within the seminiferous tubule. Note the forming spermatogonia and developed spermatozoa indicated around the Sertoli cell. FSH binding to its receptor acts via the second messenger cAMP to stimulate protein synthesis by the Sertoli cell. These proteins include the androgen-binding protein which as you can see enters the lumen of the seminiferous tubule with testosterone. Growth factors that are important for maintaining the normal function of the Leydig Cell are also produced. In the Leydig cell, LH binding to its receptor and acting via the cAMP second messenger system stimulates the production of enzymes that increase the synthesis of testosterone. This testosterone either passes into the capillary or into the seminiferous tubule.

6. Hypothalamic-pituitary-gonadal axis in the male
Hypothalamus
GnRH
Anterior Pituitary
LH and FSH
Simple flow chart showing the hypothalamic-pituitary-gonadal axis in the male. GnRH is released in a pulsatile manner, the frequency and amplitude of the pulses affect the ratio of LH/FSH synthesis by the gonadotrophs of the anterior pituitary. At this point in time it is important to stress that the anterior pituitary contains gonadotrophic cells that synthesize both LH and FSH. LH and FSH are very similar in structure with a slight difference between their  subunits. A subtle change in the release of GnRH will alter the stimulation of the mRNA that produces each specific subunit. For example high frequency release of GnRH preferentially stimulates LH synthesis over FSH. LH stimulates the Leydig Cell of the testis to produce testosterone. FSH has a major supporting role in male reproduction.
Gonadotropin Releasing Hormone
GnRH is a 10 AA peptide that is synthesized in the arcuate nucleus and stored in vesicles. It is secreted into the portal system and binds to receptors on the gonadotrophs of the anterior pituitary. It acts via IP3 and DAG to stimulate the synthesis and release of the gonadotropins.
The release of GnRH must be pulsatile in order to have effect and is controlled by dopamine, serotonin, neuropeptide Y and norepinephrine. It has a half-life of 2-4 minutes
Testes
Testosterone

7. Gonadotropin Releasing Hormone (GnRH)
10 AA peptide
Released in median eminence of hypothalamus
Secreted for a few minutes every 1-3 hours
Pulsatile (frequency and amplitude)

8. And Others Negative feedback Stress Sleep/wake cycle Hormones
Temperature
Hypothalamus
Diagram showing the regulators of GnRH secretion from the hypothalamus. These regulators change both the amplitude and the frequency of GnRH release. As stated earlier a change in frequency may change the LH/FSH synthesis ratio. As discussed earlier many factors input on the hypothalamus therefore fertility in the male can be affected by factors totally unrelated to reproductive physiology.
GnRH RELEASE
Change in amplitude
Change in frequency

9. Gonadotroph GnRH Also  LH and FSH synthesis PKC
Vesicles containing LH/FSH
Also  LH and FSH synthesis
IP3 & DAG
PKC
. Diagram showing the mechanism of action of GnRH at the gonadotroph of the anterior pituitary. GnRH acts via the IP3 / DAG second messenger system to increase the synthesis and release of LH and FSH. Remember some gonadotrophs have the ability to synthesize both hormones due to the similarity in their structures. The ratio will be determined to some extent by the frequency of GnRH release.
Release of LH/FSH via exocytosis
Ca2+

10. Increased testosterone production
Leydig Cell LH
Increased testosterone production
cAMP
Via PKA
cholesterol
Hormones from the Gonadotrophs
Luteinizing and Follicle-stimulating Hormone
LH and FSH are glycoproteins with identical  subunits and unique  subunits. LH stimulates testosterone production by the Leydig (interstitial) cells. FSH stimulates testicular growth and the production of an androgen-binding protein by the Sertoli cells (maintains high levels of testosterone in the testes). Both FSH and LH are required for the maturation of sperm.
This diagram shows the mechanism of action of LH within the Leydig cell. Acting via cAMP, the Leydig cell produces enzymes that are important for the conversion of cholesterol to testosterone. In particular LH stimulates the affinity and synthesis of cholesterol desmolase that converts cholesterol into pregnenolone in the mitochondria.
DNA transcription
testosterone

11. SYNTHESIS AND SECRETION OF TESTOSTERONE

12. Sertoli Cell FSH cAMP Via PKA Inhibin Aromatase ABP DNA transcription
Growth Factors
This diagram shows the mechanism of action of FSH within the Sertoli Cell. FSH acts via the cAMP second messenger system to stimulate the production of proteins that are important for the successful production of sperm. This includes aromatase that converts testosterone into estradiol, androgen binding protein that is important to maintain testosterone levels in the seminiferous tubules and inhibin which is important in the regulation of FSH release and hence has a role in regulating the LH/FSH ratio.
DNA transcription

13. Modulation of gene expression
At the target tissues
*Synthesis
Testosterone
*Release
*in the bloodstream
Dihydrotestosterone
(5 alpha reductase)
Release of Testosterone
Being a steroid testosterone passes across the Leydig cell membrane, some enters the bloodstream and the rest passes into the Sertoli cells.Therefore the stimulator of synthesis (LH) is the stimulator of release.An adult male will produce ~ 7mg of testosterone / day, (this decreases to 4mg/day at 70 years old).
What happens after release into the bloodstream?
If testosterone does not enter the seminiferous tubule it enters the blood. In the blood about half of the testosterone is bound to sex hormone-binding globulin (from the liver) and about35% is bound to albumin. The rest is free and therefore biologically active.
In many cases the testosterone is converted into another androgen in the target cell prior to having its effect.
This diagram shows the basic mechanism of action of testosterone at its target cell. Being a steroid hormone testosterone can pass across the plasma membrane by simple diffusion. Once inside the cell it may bind to its receptor or be converted by cytoplasmic enzymes into a different product (in this example dihydrotestosterone). Once bound to the receptor like any steroid hormone it modulates gene expression and protein synthesis.
Modulation of gene expression
proteins

14. Physiological Action of Testosterone and Associated Androgens.
An androgen is a substance that stimulates the growth of the male reproductive tract and development of secondary sex characteristics. It is important to realize that androgens affect most other tissues as well.
shows the variance in testosterone levels over a male’s life. Of particular physiological importance are the two peaks (one during fetal life, the other after puberty). The peak observed shortly after birth does occur however its role physiologically still remains in doubt.

15. Penis and scrotum hCG Accessory Organs Testosterone Testicular descent
Diagram showing the role of the testosterone released by the fetal testes. The fetal release of testosterone is important for development of the male sexual organs, testicular descent and suppression of the female sexual organs. Testosterone secretion is stimulated by hCG (human chorionic gonadotrophin).
Female suppression
Fetal testes

16. Testosterone (Adult) Reproductive Organs Spermatogenesis
Long bone fusion
Diagram showing the role of testosterone from puberty onwards. Increased secretion of LH and FSH enlarge the testes leading to elevated testosterone synthesis. This increase in androgen activity leads to the growth of the penis and scrotum. It also promotes growth and an increase in the secretory activity of the epididymis and accessory glands. It also takes part in the pubertal growth spurt (an interaction of GH, androgens, nutrition and genetics). Testosterone also fuses the epiphyseal growth plates in long bones stopping further linear growth (you can relate this when you think about the difference between gigantism and acromegaly). There is still some argument with respect to the action of testosterone with male sex drive, though testosterone receptors have been found throughout the brain. There has been shown to be no correlation between androgen levels and impotence or homosexuality.
Secondary
Sexual
Characteristics
Sex Drive

17. Secondary Sexual Characteristics Body Hair and Baldness Deep voice
Acne
. This diagram shows the secondary sexual characteristics produced by testosterone release at puberty and throughout adult life. It produces hair on the face, chest and upper pubic triangle. It causes a deepening of the voice due to growth of the larynx and vocal cord thickening. In concert with growth hormone testosterone stimulates muscle mass. It also increases the secretory activity of the sebaceous glands leading to acne.
Protein formation
Muscle
development
Bone size and
strength

18. Some testosterone converted into estrogens
Hypothalamus
Some testosterone converted into estrogens
GnRH
Anterior Pituitary LH
FSH
Leydig
cell
Sertoli Cell
This diagram shows the negative feedback regulation of testosterone secretion by the gonads. Testosterone inhibits the secretion of GnRH from the hypothalamus and the secretion of LH from the anterior pituitary (note that some of the testosterone is converted into estradiol in the gonadotroph prior to inhibiting LH). Inhibin inhibits the secretion of FSH. This negative feedback system is extremely important as you now know that the amount of LH and FSH synthesized by the gonadotroph is also related to the frequency and amplitude of GnRH release.
Testosterone
Inhibin

19. Formation of the Ejaculate and the Role of the Accessory Organs
As the sperm passes through the epididymus it matures (due to dihydrotestosterone), and becomes more concentrated (fluid reabsorption). Capacitation
The sperm is then stored in the epididymus and vas deferens waiting for ejaculation.
Sperm can remain viable here for up to 60 days as nutrition is supplied and inhibitory factors decrease their energy use.
On ejaculation the sperm (and fluid) passes through the vas deferens, ejaculatory ducts and finally through the urethra. During this passage the fluid content is increased due to secretions from the accessory organs

20. Sperm, fructose, prostaglandins, clotting precursors
Epididymus
vas deferens
10%
Sperm
storage
Seminal vesicles
Sperm, fructose, prostaglandins, clotting precursors
60%
Prostate gland
This diagram is a summary of the substances added to the sperm as it passes through the male ductal system on the way to being ejaculated. As you can see approximately 10% of the ejaculated semen is made up of the sperm and fluid stored in the epididymus. As the sperm moves through the male reproductive tract on the stimulus of ejaculation it first passes the seminal vesicles, where they release their fluid into the ductus deferens (this makes up between 60-75% of total semen volume).
Fructose - primary energy source for ejaculated sperm
Prostaglandins - stimulate contractions of the smooth muscle in both the male and female reproductive tracts
Fibrinogen - fibrin precursor (clotting precursor)
Volume - the volume is important to dilute sperm and make semen less sticky
The semen then passes by the prostate gland that releases its fluid near the beginning of the urethra. This fluid makes up about 30% of total semen volume. This fluid contains:
alkaline substances - to neutralize the acidic vaginal secretions
clotting enzymes - act on fibrinogen to clot the semen keeping it in the vagina
fibrinolysin - breaks down clot after withdrawal, releasing sperm
During intercourse the Bulbourethral Gland secretes mucus to help with lubrication during sexual intercourse.
30%
+ alkalization, semen clotters
And unclotters

21. The male sex act
•The male must have an erection and ejaculate in order to complete the sex act.
PSYCHOLOGICAL
AND/OR PHYSICAL
STIMULI
Parasympathetic
Activity
Sympathetic
Activity
Via NO and/or ACh
Diagram showing the neural control of the erection reflex. The major controller of the erection is the parasympathetic nervous system. ACh may release NO via M3 receptors and/or the NO may also be released from the postganglionic terminal with ACh. The important thing is that an elevated parasympathetic activity increases the activity of NO. NO causes dilation of the penile arterioles by causing a cascade of reactions that eventually lead to a decrease in intracellular calcium and/or a decrease in myosin light chain activity.
An erection may best be described as engorgement of the penis erectile tissue with blood. This is due to parasympathetic dilation of the penile arterioles increasing blood flow to the penis and at the same time mechanical compression of the penile veins decreasing blood flow out.
Vasodilation
Erection

22. Ejaculation Emission Expulsion
Genital duct / accessory organ contraction (sympathetic stimulation)
Vas deferens, prostate, seminal vesicles
Mix with mucus in urethra producing semen
Expulsion
Semen expelled by rhythmic skeletal muscle contraction at base of penis
Ejaculation
Ejaculation is the forceful expulsion of semen into the urethra and out of the penis. It may be separated into two phases, emission and expulsion.
Emission
We have looked at emission with respect to the makeup of the semen that leaves the penis. The stimulator of emission is the sympathetic nervous system that produces sequential contraction of the smooth muscle of the prostate, reproductive ducts and seminal vesicles. This causes the stored sperm in the epididymus/vas deferens to be forced into the reproductive ducts and receive fluid from the contracted seminal vesicles and prostate glands. This leads to the semen entering the urethra.
Expulsion
The filling of urethra with the semen produces nerve impulses that cause contraction of skeletal muscles at base of the penis. This increases the pressure in the penis causing the expulsion of semen out of the penis.

23. Hypogonadism Non-functional testes in fetus Loss of testes pre-puberty
Lead to development of female sex organs
Loss of testes pre-puberty
Maintain infantile sex organs and characteristics
Bones less strong but longer
Maybe taller than other men
Medical problems
Hypogonadism
This is when the testes are non-functional. There is no steroidogenesis in the testes and hence no spermatogenesis. The effects of hypogonadism are dependent upon when the problem is initiated.
Not functional ever. There is no development of male sexual organs. In fact female sexual organs develop as this is what happens if there are no sex hormones present.
Stop functioning prior to puberty. There is no development of secondary sexual characteristics. The sexual organs to do not mature. Lack of testosterone means that there is a delay in epiphyseal plate fusion meaning long bones are longer.
Stop functioning after puberty. May decrease the size of sexual organs, reverse some of the secondary sexual characteristics and enlarge breasts. May cause erectile dysfunction and infertility.

24. (cont) Loss of testes post-puberty
Slight decrease in size of sexual organs
Slight increase in voice pitch
Loss of bone and protein build up
Slight loss of sexual desire
Less easy for erection
Ejaculation rarely occurs

25. Infertility Sperm count Sperm morphology and motility
Should have ~ 60 million sperm / ml of semen(2-5ml)
If below 20 million / ml are said to be infertile
Sperm morphology and motility
Abnormal shape of sperm
Lack of motility
Infertility
In order to be fertile the male requires enough sperm that are both motile and have the correct morphology. These sperm have to be able to be ejected from the male into the female close to the cervix in order to maximize the chances for pregnancy.
Impotence
This is the inability to produce or maintain an erection. In most cases it is due to problems with blood flow.
Impotence
This is the inability to produce or maintain an erection. In most cases it is due to problems with blood flow.

26. Neurological Examination:
An 8 year old boy visited his pediatrician, and his mother reported that he was in good health until about two weeks ago. He describes that his initial symptoms include a mild bifrontal headache, which has become progressively worse. During the last few days, he developed nausea and bouts of occasional projectile vomiting accompanying the headaches. Furthermore, he recently noticed that he has tremendous difficulty when walking down the stairs from his bedroom to the kitchen and reported difficulties in
sleeping. No family history of abnormal development or mental retardation exists. He has two perfectly healthy younger brothers.
General Examination:
This 8 year boy presents with pronounced pubic hair growth, a low pitched voice, enlarged genitalia, and acne on his forehead. Cardiac and respiratory examinations were unremarkable.
Neurological Examination:
Patient is alert and oriented x 3. No receptive or expressive aphasias were noted. Pupillary light reflex was intact bilaterally. Both the left and right optic discs appeared more pale than normal. Downward gaze (while the eyes were adducted) was impaired bilaterally.
As noted, the biologic events at puberty are set in motion by the onset of pulsatile activity in the hypothalamic-anterior pituitary axis. In turn, this pulsatile, or bursting, activity causes the testes and ovaries to secrete their respective sex hormones. Pulsatility of the hypothalamic-pituitary axis is required for normal reproductive function, as illustrated by the treatment of persons with delayed puberty caused by GnRH deficiency. If a GnRH analogue is administered in intermittent pulses to replicate the normal pulsatile secretory pattern, puberty is initiated and reproductive function is established. However, if a long-acting GnRH analogue is administered, puberty is not initiated
In boys, puberty is associated with activation of the hypothalamic-pituitary axis, Leydig cell proliferation in the testes, and increased synthesis and secretion of testosterone by the Leydig cells. There is growth of the testes, largely because of an increased number of seminiferous tubules. There is growth of the sex accessory organs such as the prostate. There is a pronounced linear growth spurt, and the epiphyses close when adult height is attained. As plasma levels of testosterone increase, pubic and axillary hair appears, and there is growth of the penis, lowering of the voice, and initiation of spermatogenesis.