male infertility

The focus of attention

Today’s focus

What we know

Fig. 46.8

Reproductive Anatomy of the Human Male

The male reproductive system comprises of a pair of testes that are present in a thin-walled sac called the scrotum. . A temperature 2-3 degrees lower is ideal for the production of sperms. Internally, the testis is lobed. There are 15-20 lobes, each having a network of seminiferous tubules and the interstitial cells between the tubules.

The seminiferous tubules produce sperms that are passed along the tubules The sperms are produced by a process called the spermatogenesis. The interstitial cells are also called the Leydig cells and they secrete the hormone testosterone.

Testes

From the seminiferous tubules, the sperms are passed into a network of 10-12 ducts called vasa efferentia. They are then passed into a highly coiled tubular part called the epididymis.

The sperms from the epididymis pass into a distinct tube called the vas deferens, also called the sperm duct. . Vas deferens is joined by the duct from the seminal vesicle to form the ejaculatory duct. The duct then passes through the prostrate glands and opens into the urethra.

Duct System

Glands

The various glands associated with the male reproductive system are as follows:

Seminal vesiclesProstrate glandCowper's glandsPenis

Seminal Vesicles A pair of seminal vesicles are glands that are present behind the urinary bladder. Each sperm duct has the seminal vesicle of its side secreting a fluid into the common ejaculatory duct. This fluid along with the sperms is called the semen, a milky fluid.

Prostate Gland It is a bi-lobed gland near the opening of the urethra. The prostate gland also pours its secretion into the urethra.

Cowper's Glands They are a pair of small ovoid glands that secrete lubricating fluid into the urethra just before it enters the penis.

Penis: Penis is a muscular organ containing erectile tissue. The tissue is richly supplied with blood vessels.

Glands

Production Of Sperm - Spermatogenesis

Fig. 46.11

Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings

Sperm

Sperm

55-65 µm in length

Three parts head, neck and tail. On the outside of the anterior two thirds of the head is a thick cap called the acrosome that is formed mainly from the Golgi apparatus. It contains enzymes similar to those found in lysosomes hyaluronidase and powerful proteolytic enzymes. These play important roles in allowing the sperm to enter the ovum and fertilize it.

Sperm

The tail of the sperm, called the flagellum, has threemajor components: (1) A central skeleton constructed of 11 microtubules, collectively

called the Axoneme(2) A thin cell membrane covering the Axoneme(3) A collection of mitochondria surrounding the axoneme in the

proximal portion of the tail (called the body of the tail) Normal sperm move in a fluid medium at a velocityof 1 to 4 mm/min.

Regulation of Sex Hormone Secretion and Sperm Production

This process begins during puberty

Gonadotropin releasing hormone (GnRH) from the hypothalamus stimulates the production of the follicle-stimulating hormone (FHS) and luteinizing hormone (LH) from the anterior pituitary.

Testes respond to FSH by initializing spermatogenesis.

LH assists spermatogenesis and production of testosterone.

Inhibin hormone controls production of sperm count

Male infertility

Male infertility of unknown origin is a condition in which fertility impairment occurs spontaneously or due to an obscure or unknown cause

• It includes 2 categories,1. Unexplained male infertility &

2. Idiopathic male infertility.

• The dividing line between them is semen analysis, which is normal in the unexplained category and abnormal in idiopathic infertility.

Terminologies

1.Azoospermia : Absence of Sperm

2.Oligozoospermia : Low Sperm Count

3.Asthenozoospermia : Sperm with Poor Motility 4.Teratozoospermia : Abnormal shape of Sperm

Causes - male infertility

When there is structural abnormality in the spermsWhen there is structural abnormality in the sperms

When there is functional abnormality in the spermsWhen there is functional abnormality in the sperms

Causes - male infertility

When Number is < 1m/ejaculateWhen Number is < 1m/ejaculate

When Progression is < 2/4When Progression is < 2/4

When Motility is < 20%When Motility is < 20%

When Abnormal forms are > 85%

When Abnormal forms are > 85%

Causes - oxidative stress

Oxidative stress (OS) is the imbalance between the production of reactive oxygen species (ROS) by the spermatozoa and leukocytes & the antioxidant capacity of the seminal plasma. 1. The primary source of ROS production in infertile

patients is the immature spermatozoa.

2. Oxidative stress can damage the DNA of the spermatozoa & prevent them fertilizing an egg.

3. Reactive oxygen species (ROS) includes oxygen ions, free radicals and peroxides.

Causes-inadequate progression

Grade 0 is no movementGrade 0 is no movement

Grade 2 is slow movement but not straightGrade 2 is slow movement but not straight

Grade 1 is sluggish movementGrade 1 is sluggish movement

Grade 3 is movement in a straight lineGrade 3 is movement in a straight line

Grade 4 is terrific speed.Grade 4 is terrific speed.

ROS – In Male Infertility

ROS – In male infertility

Role of ROS in male infertility

1. Idiopathic oxidative stress has been linked with male factor infertility as it is known to contribute to defective spermatogenesis leading to male factor infertility

2. Uncontrolled & excessive production of ROS overwhelms the limited antioxidant defenses in semen resulting in seminal oxidative stress

3. Seminal oxidative stress correlates negatively with sperm concentration, motility and function - adversely affecting fusion events required for fertilization.

Superoxide anion, hydroxyl radical and hydrogen peroxide are major reactive oxygen species (ROS) present in seminal plasma.

ROS - Role in male infertility

ROS are produced by the spermatozoa (especially damaged spermatozoa) & seminal leucocytes - most notably granulocytes.

ROS directly damage sperm DNA, compromising the

paternal genomic contribution to the embryo

This, in turn, reduces the sperm’s motility and ability to fuse with the oocyte.

Reports have indicated that high levels of ROS are detected in semen samples of 25-40% of infertile men

& seems to be the leading cause infertility by 2 principal mechanisms:

ROS damage the sperm membrane by causing

lipid peroxidation of sperm membrane

Body's defense against ROS

To maintain normal cell

function

Excess ROS is continuously inactivated by seminal plasma

antioxidants

Glutathione peroxidase

The seminal plasma antioxidants block the formation of new ROS or act as scavengers and remove ROS already generated

Natural antioxidant enzyme systems include

CatalaseSuperoxide dismutase

Underlying facts on anti-oxidants

However in conditions of oxidative stress, production of ROS overwhelms antioxidant defence.

However in conditions of oxidative stress, production of ROS overwhelms antioxidant defence.

Hence, there is a pressing need for external antioxidant support!

Hence, there is a pressing need for external antioxidant support!

Antioxidants are the most important defence against free radical induced infertility

Antioxidants are the most important defence against free radical induced infertility

The several antioxidant strategies produced by the human body protect itself from ROS damage

The several antioxidant strategies produced by the human body protect itself from ROS damage

This permits normal oxidative metabolism to occur without damaging the cells, while still allowing for normal ROS-mediated cellular responses such as destruction of infectious pathogens and intracellular signalling

This permits normal oxidative metabolism to occur without damaging the cells, while still allowing for normal ROS-mediated cellular responses such as destruction of infectious pathogens and intracellular signalling

The need of the day

Levels of ROS within semen can be ↓ by augmenting the scavenging capacity of seminal plasma, by antioxidant supplement.

Antioxidant supplements boost sperm count, morphology and sperm motility and prevent DNA damage to sperm

Antioxidant supplements boost sperm count, morphology and sperm motility and prevent DNA damage to sperm

But, what can antioxidant do to the problem of male infertility?But, what can antioxidant do to the problem of male infertility?

The therapeutic supplementation in male

infertility

Clomiphene – Role in male fertility

Clomiphene citrate influences spermatogenesis and also improves semen quality

Antioxidants in the therapy of male infertility

Because ROS have been associated with sperm DNA damage, investigators have studied possible protective roles of antioxidants in preventing or treating sperm DNA damage.

Antioxidants in the therapy of male infertility

82% trials showed an improvement in either sperm quality or pregnancy rate after antioxidant therapy.

10 trials examined pregnancy rate and 6 showed a significant improvement after antioxidant therapy.

The use of oral antioxidants in infertile men could improve sperm quality and pregnancy rates.

Antioxidants in the therapy of male infertility

UbidecarenoneCarotenoids (Lycopene)Omega 3 fatty acidsCarnitine / Levo CarnitineVitamin E & Vitamin CSeleniumGlutathione N-acetyl cysteineL ArginineTrace Metals like ZincVitamin B12

Ubidecarenone

Also known as Coenzyme Q10, ubiquinone, coenzyme Q, and abbreviated at times to CoQ10 , CoQ, Q10, or Q

Component of the electron transport chain and participates in aerobic cellular respiration, generating energy as ATP.

Unique capacity of this molecule:

To exist in a completely oxidized form Enables it to function in the electron transport chain

To exist in a reduced form Enables it to function as an antioxidant

Ubidecarenone - Role in male fertility

In sperm cells, Co Q10 is concentrated in the mitochondrial mid-piece, where it is involved in energy production.

It also functions as an antioxidant, preventing lipid peroxidation of sperm membranes.

According to studies, Ubidecarenone shows significant increase in:

sperm motility

sperm density

improvement in fertilization rate

Lycopene - Role in male fertility

Bright red carotenoid pigment, phytochemical and powerful antioxidant with a major role in the management of idiopathic male infertility.

Most efficient oxygen & free radical quencher and prime carotenoid in plasma / other tissues

It is a component of human redox defence mechanism against free radicals

Found in high concentrations in the testes and seminal plasma

Decreased levels have been demonstrated in men suffering from infertility.

Lycopene - Role in male fertility

Studies suggest efficacy of lycopene in male infertility as it improves.

Sperm Concentration Sperm Motility Sperm Morphology

Mixed caretenoids - Role in male fertility

Carotenoids work synergistically with Se and vitaminE

Mixed carotenoids, taken with vitamins C and E, may help protect sperm from damage by free radicals as it improves -

Sperm Motility Sperm Morphology Sperm Concentration and Improved Fertility rates

Omega-3 fatty acids - Role in male fertility

Omega−3 fatty acids includes eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

DHA (Docosahexaenoic acid) is essential for male fertility.

Omega-3 fatty acids are abundant in the sperm with DHA being abundant in the sperm tail to have significant effect in sperm motility.

Its deficiency is linked to low sperm count and infertility.

Omega-3 fatty acids - Role in male fertility

Normal sperm cells contain an arc-like structure called the acrosome. Acrosome is critical in fertilization because it houses, organizes, and concentrates a variety of enzymes that sperms use to penetrate egg.

DHA is essential in fusing the building blocks of the acrosome together.

Without DHA, this vital structure does not form and sperm cells don't work

DHA plays a major role in regulating membrane fluidity in sperm + regulation of spermatogenesis

Omega-3 fatty acids - Role in male fertility

Wheat germ oil - Role in male fertility

Source of Vitamin E and primary function is as an Antioxidant

It is a major chain-breaking antioxidant in the sperm membranes

Protects the sperm membrane from oxidative damage and increased levels are associated with low levels of reactive oxygen species.

It scavenges all 3 types of free radicals, viz. Superoxide, Hydrogen peroxide and hydroxyl radicals.

Wheat germ oil - Role in male fertility

Vitamin E enhances sperm performance Vitamin E protects spermatozoa from:

1. Oxidative damage2. Loss of motility

Calcium ascorbate – Role in male fertility

Natural form of Vitamin C that is a water-soluble ROS scavenger with high potency.

Readily absorbed in the blood stream than the other forms of calcium.

It is a strong antioxidant destroying free radicals in the body and protects human spermatozoa against endogenous oxidative damage by neutralising :1. Hydroxyl2. Superoxide, & 3. Hydrogen peroxide radicals

Calcium ascorbate – Role in male fertility

Vitamin C Prevents sperm agglutination. Vitamins C and E act synergistically to protect

against peroxidative attack on spermatozoa.

Vitamin B 12 - Role in Male Fertility

Vitamin B12 is important in cellular replication, especially for the synthesis of RNA and DNA

Deficiency states have been associated with decreased sperm count and motility

B12 supplementation improves sperm parameters such as:1. Sperm concentration,

2. Sperm count and

3. Sperm motility.

Selenium - Role in Male Fertility

Selenium is a nonmetal & a trace mineral that is essential to good health but required only in small amounts.

Its antioxidant properties helps prevent cellular damage from free radicals

Protects against oxidative sperm DNA damage and is required for: 1. Normal testicular development

2. Spermatogenesis

3. Motility and function

Selenium - Role in Male Fertility

Essential for formation of phospholipid hydroperoxide glutathione peroxidase - an enzyme present in spermatids which becomes a structural protein comprising over 50 % of the mitochondrial capsule in the mid-piece of mature spermatozoa.

Deficiency leads to instability of the mid-piece, resulting in Defective motility Breakage of the spermatozoal mid-piece and Increased morphological abnormalities, mostly affecting the

sperm head

Zinc - Role in male fertility

Zinc is a trace mineral essential for normal functioning of the male reproductive system.

Zinc levels are generally lower in infertile men with diminished sperm count

Zinc supplementation shows improvement in sperm quality, sperm motility, fertilisation capacity and a reduction in the incidence of anti-sperm antibodies.

Zinc - Role in male fertility

Zinc is found in high concentration in sperm, and is vital in making the outer layer of the sperm, as well as the tail.

Zinc deficiency is associated with decreased testosterone levels and sperm count

Administration of exogenous systemic zinc to males with zinc deficiency can improve sperm production and sperm motility.

Supplementing zinc in the diet can re-establish testosterone and sperm count levels to acceptable levels

Zinc - Role in male fertility

Zinc therapy results in significant improvement in sperm quality with increase in sperm density, progressive motility and improve conception and pregnancy outcome

Piperine

Piperine is an alkaloid - a standardized extract from the fruits of Piper nigrum L. (black pepper) or Piper longum L. (long pepper)

Piperine may be co administered with various nutrients for human health.

It has antioxidant activity It lowers lipid peroxidation It increases the plasma levels of Coenzyme Q10

following oral supplementation.

Levocarnitine: Provide energetic substrate for spermatozoa. Sucessful maturation of sperm. Increases spermatozoa per ejaculate Increase in progressive linear sperm motility in idiopathic asthenospermia.

L Arginine: Precursor of nitric oxide, which effectively improves sexual performance. Effective even in erectile dysfunction cases Increase sperm count, quality, and fertility