Male Infertility and Its Solutions

Anatomy and Physiology

Testes (ovaries)

The testicles are a pair of glands located in the ovarian sacks called the scrotum. The testicles are responsible for the secretion of the hormone testosterone (male hormone), which promotes the development of male characteristics, and for the production of sperm cells. The testes are made up of filamentous tubules, called seminiferous tubules, where sperm cells are produced, and Leydig cells, which secrete the hormone testosterone, located around these tubules. Sperm ejaculate into the vas deferens (sperm duct) through a structure called the epididymis, located at the top of the testicles.

Although Leydig cells, which produce the male hormone, are very durable cells, seminiferous tubules, which produce sperm, are very delicate structures. Therefore, most men with infertility do not have problems with the development of secondary sex characteristics.

Sperm Production and Hormonal Control

Hormones control sperm production. The pituitary gland, located in the lower part of the brain, produces the hormones FSH and LH.

FSH: Stimulates sperm production from the seminiferous tubules.

LH: Stimulates testosterone production from Leydig cells.

Testosterone: Essential for sperm production and the development of masculine characteristics.

The germ cells in the lower part of the seminiferous tubules begin to develop and spermatogonia, spermatocytes, spermatids and spermatozoa are formed in the 64-day process called spermatogenesis. The sperm cells are nourished by Sertoli cells in the tubules during their development and maturation. The matured sperm cells come to the upper part of the seminiferous tubules and gain motility as they pass through the epididymis.

Fluids secreted by the seminal glands and the prostate gland are also mixed with semen before ejaculation. The first part of semen contains zinc, fatty compounds, amino group acids and enzymes. The second part contains substances that contract the uterus and tubes, nourish the sperm and neutralize the acid environment of the vagina so that the sperm can travel through the female reproductive organs.

Structure of the sperm cell

The sperm cell is 0.05 mm long and consists of three parts. The head of the sperm cell contains the genetic material. The neck provides the energy needed for sperm movement and the tail provides sperm movement.

Causes of Male Infertility

Male reproductive health is affected by hormones, sperm production, sperm transport in the sperm ducts and sexual function. Disorders in any of these can cause infertility.

Cryptorchism (undescended testicle)

At birth or within one year after birth at the latest, the testicles descend into the scrotum (ovarian sac). When one or both testicles do not descend into the scrotum, this is called cryptorchism. In these cases, sperm production is impaired because the testicles that remain above the abdomen are exposed to higher temperatures. In cases of bilateral undescended testicles, azoospermia (no sperm in semen) can be seen. In cases of undescended testicles, the risk of developing testicular tumors in the future is also high. If the testicles are surgically lowered into the scrotum between the ages of 1-2 years, reproductive health is not adversely affected in the future. Cases that are not treated early can have children with assisted reproductive techniques.

Testicular Tumors

Infertility is common in men being treated for testicular tumors. Drugs used for chemotherapy and radiotherapy negatively affect sperm production. Sperm samples taken from these cases before treatment are frozen and stored.

Testicular Trauma (injury)

Injuries to the testicles can result in infertility. After the trauma, Sertoli cells in the testicles enter the bloodstream and cause the formation of antisperm antibodies and infertility.

Varicocele

They are varicose veins that form around the testicles in the scrotum. Enlarged veins are seen in 15% of men. Not all men with varicocele are infertile, but about one third of men evaluated for infertility have varicocele. When the valves of the spermatic veins are absent or malfunctioning, the blood escapes backwards and pools. In 90% of varicocele cases, it is seen on the left side.

Varicocele;

By causing an increase in heat in the scrotum due to slowing of blood flow,

Due to the reverse blood flow from the left adrenal gland, the testes are exposed to high levels of toxic waste,

By causing a disturbance in the balance of reproductive hormones,

It causes infertility.

When varicocele is suspected during the examination, the diagnosis is confirmed by Doppler Ultrasonography.

Infections

Infections in the reproductive organs can lead to infertility. Inflammatory reactions during gonorrhea, tuberculosis and some bacterial infections can cause blockages in the reproductive tract. Bacterial infections can cause infertility by impairing sperm movement and damaging developing sperm cells. Testicular involvement and permanent damage to the seminiferous tubules can occur, especially when mumps is acquired late in life.

Chlamydia, mycoplasma and ureoplasma infections, which are commonly transmitted through sexual contact, can also cause infertility by impairing sperm quality. Early diagnosis and treatment of these infections is important.

Systemic Diseases

High fevers have a negative impact on reproductive health. High fever damages sperm cells within a few hours. After about 3-4 weeks, a man with a high fever has a decrease in the number of sperms and the proportion of sperms with a normal structure. Reproductive hormones decrease in men with kidney and liver disease. Impotence (impotence), sexual reluctance, decrease in sperm production are seen in kidney diseases. Especially in patients undergoing frequent dialysis, hormonal imbalance and decrease in sperm production occur. Deterioration in sperm quality can also be seen after some allergic reactions.

Obstruction in the Reproductive Ducts

Blockages in the reproductive ducts prevent sperm from coming out. Infections, injuries, surgical procedures can cause blockages in the ducts. In some men, the ducts are congenitally absent. In cases of complete blockage on both sides, there are no sperm in the semen. FSH levels are normal in these cases.

Retrograde Ejaculation (Back Ejaculation)

Semen flows backwards into the bladder during ejaculation. In these cases, sometimes very little semen flows out during ejaculation and sometimes none at all. This condition can occur after diabetes, multiple sclerosis, bladder neck injuries and prostate surgeries or due to certain medications used in the treatment of hypertension (high blood pressure) and depression. Sperm can be extracted from urine samples taken from these cases and vaccination can be performed.

 

Neurogenic (Nervous System) Causes

Spinal cord injuries cause lack of ejaculation, erection problems, lack of sexual intercourse and reduced sperm production. Ejaculation can be realized in these cases with electrical stimulation.

Endocrine Disorders

The production and release of reproductive hormones is controlled by the hypothalamus, pituitary gland and testes. The pituitary gland secretes LH (luteinizing hormone) and FSH (follicle stimulating hormone).The release of these hormones is controlled by a hormone called GNRH, which is released from the hypothalamus.The testes produce testosterone, which is converted into androgens (male hormones) and estrogens (female hormones) in tissues outside the genital organs.

Hypogonadotropic Hypogonadism; In this condition, which is usually congenital, LH and FSH levels decrease due to GNRH deficiency. In these cases, there is also an olfactory problem.

Kalman Syndrome; In this syndrome where isolated GNRH deficiency is seen, midline defects such as inability to smell, small penis, undescended testicles and cleft palate and cleft lip can also be seen.

Isolated LH Deficiency; In this condition, also known as Önük syndrome, although the testes are large, secondary sex characteristics are not well developed. Hair distribution and density on the body is like pre-puberty, skeletal system development is not good. LH and testosterone levels are low, FSH level may be normal in this condition, which is seen due to the pituitary gland not working.

Hyperprolactinemia or Postpubertal Gonadotropin Deficiency; due to tumors in the pituitary gland, breasts enlarge, milk comes, impotence is observed, sperm production decreases. Testicles shrink and testosterone level decreases. These tumors are diagnosed by tomography and magnetic resonance imaging.

Apart from these, disorders in the adrenal gland, some rare syndromes, hemachromatosis (a disease with iron accumulation in the body), obesity, liver diseases, adrenal gland tumors can cause hormonal disorders.

Genetic Disorders

Due to genetic disorders, testicular development and sperm production disorders and hormonal imbalance may be observed.

Kleinfelter Syndrome; In this condition, which occurs in one in five hundred births, there is an extra X sex chromosome in addition to XY sex chromosomes. In these men with 47 chromosomes, testicles are small and hard, and secondary sex characteristics are underdeveloped. In these cases there is no sperm production. In the milder form of this disease, called mosaic, sperm production may occur. Many disorders of the sex chromosomes cause infertility. In many of these cases, the testes and sperm production are affected. Genetic disorders that do not affect the sex chromosomes can also cause infertility. Infertility is common in certain muscle diseases, sickle cell anemia, Mediterranean anemia and bladder disorders. In cases of cystic fibrosis, another disease accompanied by infertility, the amount of semen and sperm count are low. In these cases, sperm ducts are not developed.

Sexual Function Disorders

Ejaculation problems such as impotence, premature or delayed ejaculation should be considered when evaluating male infertility.

Risk Factors in Male Infertility

Environmental factors and lifestyle affect reproductive health;

Smoking negatively affects sperm count, motility and structure. It has been determined that the likelihood of miscarriage increases in the wives of men who smoke.

Alcohol causes impotence and impaired sperm production. In cases of chronic alcoholism, the testicles shrink and testosterone production is impaired.

Drugs have a negative effect on sperm quality and production. These substances also cause hormonal imbalances.

Drugs; drugs used in the treatment of many diseases have a negative effect on sperm production, but this effect is temporary. Many antibiotics, parasitic drugs, some drugs used in the treatment of depression, stomach ulcers, hypertension and allergic diseases have been shown to negatively affect male reproductive health.

Chemotherapy; drugs used in cancer treatment damage sperm production. Some of these drugs may have a permanent effect. Before chemotherapy, sperm samples can be taken from these patients and frozen for future use.

Radiation; sperm producing cells in the testicles are very sensitive to radiation. The degree and permanence of the damage depends on the radiation dose. In patients who have undergone radiotherapy, sperm production may resume within 3-5 years.

High temperatures, especially saunas and hot water baths, have a negative effect on sperm production.

Pesticides negatively affect sperm production.

Evaluation and Diagnosis of Male Infertility

Spouses should consult the physician together for infertility evaluation. Knowing what to do before consulting a physician will put you at ease and prevent unnecessary stress. A detailed medical history, physical examination and semen analysis are the most important steps in the evaluation of male infertility.

Medical History:

During the first consultation, your doctor will ask you many questions to get detailed information about your general health, reproductive health and sexual life.

  • General health and systemic diseases
  • Whether you had a mumps infection after puberty
  • History of trauma to the testicles
  • History of undescended testicle
  • Presence of inguinal hernia (inguinal hernia)
  • Infections of the reproductive organs and urinary tract
  • Infections transmitted through sexual contact
  • Previous operations on reproductive organs
  • History of radiotherapy and chemotherapy
  • Vasectomy (surgical sterilization)
  • Frequent recurrent respiratory infections
  • Olfactory impairment
  • Whether there are complaints such as visual disturbances and milk coming from the breasts
  • Frequency of sexual intercourse
  • Age when puberty begins
  • Sexual dysfunction

Other Factors

Smoking and alcohol use

All prescription or over-the-counter medicines you have used recently

Radiation and other environmental toxins you are exposed to

Toxins you are exposed to at work and other factors that can affect your reproductive health

High heat

History of infertility:

Duration of infertility

Examinations and treatments performed on your partner in terms of infertility

Physical Examination

The physical examination will identify abnormalities in the testicles, penis, prostate gland, varicocele and secondary sex characteristics that lead to infertility. Your genital organs are examined to assess the development of the testicles and penis. Body hair distribution, skeletal and muscular development are examined.

The growth of breasts in men is called gynecomastia. Gynecomastia can be seen due to hormonal disorders. Systemic diseases such as cirrhosis and liver failure also cause gynecomastia.

Tests for Diagnosis of Infertility

Semen analysis, urine analysis and hormone analysis are the first investigations that should be performed in the evaluation of male infertility.

Semen Analysis:

The most important test for male infertility is semen analysis. Things to consider when giving semen for analysis;

2-5 days of sexual abstinence

Taking a clean container, e.g. with masturbation

Not using substances such as saliva, soap or shampoo to lubricate the sample

It is appropriate to deliver the sample to the laboratory where it will be examined within 60 minutes at the latest, especially in cold weather, and to transport the sperm sample by contact with the body.

The sperm analysis evaluates the number of sperm per milliliter, their motility and structure. The amount, acidity and round cells in the semen are also determined. If necessary, anti-sperm antibody tests and microbiological examinations are performed.

Normal Sperm Analysis

Semen quantity: 1.5 – 6.5 ml

Sperm concentration 20 million/ml and more

Sperm motility: 50% or more

Sperm morphology (structure): 14% or more sperm with normal structure (according to Kruger criteria)

The presence of the above values after sperm analysis does not necessarily indicate that pregnancy will occur. The wives of men with a sperm concentration of 10 million /ml may become pregnant, while the wives of men with a sperm concentration of 60 million /ml may not become pregnant.  Since sperm production is affected by many factors such as heat, smoking, alcohol, drugs and infections, the analysis of abnormal samples should be repeated two or three times at one month intervals.

Microscopy

Microscopic examination is very important in evaluating the properties of semen. The number, motility and structure of sperm are evaluated with a microscope. In addition, special microscopes such as fluorescence microscopy can be used to evaluate the acrosome reaction of sperms and to study their genetic material. Electron microscopy provides detailed information about the structure of sperm.

Morphology

  • The normal sperm is an oval-headed cell with an easily recognizable acrosome and a symmetrical head and tail. The first part of the tail thickens a little and forms the play part. Sperm are stained with special dyes to evaluate their structure.
  • According to Kruger’s strict criteria, a normal sperm cell
  • 2.5 – 3.5 µm in diameter with a smooth oval-shaped head.
  • The acrosome makes up 40-60% of the head.
  • The neck and tail are smooth, the tail is 50-60 µm long.

Defects in sperm structure prevent fertilization. Structural defects can be seen in the head, neck and tail of the sperm. Usually more than one part of the sperm is affected.

Agglutination

Agglutination is the clumping of sperms by binding to each other due to the presence of antibodies in semen. When agglutination occurs, sperm motility and the ability to fertilize the egg decrease.

Acrosome reaction

The acrosome is the structure covering 50-70% of the front of the sperm head. The acrosome reaction occurs when the acrosome membrane combines with the plasma membrane and this reaction enables the sperm to bind to the egg membrane. Today, acrosome reaction tests can be performed using different methods to get an idea about the sperm’s ability to fertilize the egg.

Antisperm antibodies

Antisperm antibodies are found in the serum, semen and cervical mucus (cervical secretion) of men and women. Antisperm antibodies reduce sperm motility and the proportion of viable sperm and can cause infertility by inhibiting the acrosome reaction and sperm binding to the egg. IgG and IgM type antibodies are found in serum and IgA type antibodies are found in semen and cervical mucus. When agglutination is detected in semen analysis, testing to detect the presence of antisperm antibodies is recommended.

Hypo-osmotic Swelling test

It is a test used to determine sperm viability. Since the integrity of the membrane of the live sperm cell is intact, it enters the cell in low osmotic pressure environments and as a result, swelling is seen in the sperm tail. It is also used to select live sperm during microinjection when sperm motility is very low.

Testicular (ovarian) biopsy

Testicular biopsy is performed in patients with azoospermia or severe oligoospermia to determine obstructive and non-obstructive (obstruction-related and non-obstruction-related) causes. Since hematoma (bleeding) due to trauma and destruction of testicular tissue may occur after testicular biopsy and sperm obtained from testicular tissue can be used in the microinjection process today, diagnostic and therapeutic biopsy can be performed at the same time.

Evaluation of testicular biopsy;

Normal spermatogenesis; normal sperm production, in cases of azoospermia or severe oligozoospermia, such a biopsy result suggests obstruction in the sperm ducts.

Hypospermatogenesis; although all cells in different stages of sperm production are present, production is reduced. It can be seen due to disorders in the hypothalamus, pituitary gland and testicular axis.

Mastural arousal is a pause in sperm production at a certain stage.

Sertoli cell only syndrome is the complete or partial absence of sperm-producing cells. It may be due to cancer treatment or previous infections.

Tubular fibrosis is a condition in which the destruction of testicular tissue is advanced. Sperm producing cells and Sertoli cells are lost and Leydig cells are reduced. This may be due to radiation therapy, mumps infection, undescended testicle and lack of oxygen to the testicular tissue.

Endocrinologic examination

Male sex hormones are needed for sperm production. These hormones and their effects are shown in the table below.

 HORMONE    IMPACT
GnRH  It secretes the hormones FSH and LH. It is secreted from the hypothalamus in the brain.
FSH  Stimulates Sertoli cells in the testis to produce sperm. Secreted by the pituitary gland.
LH  Synthesizes testosterone in Leydig cells and maintains sperm production. Secreted by the pituitary gland.
Prolactin   Increases the effect of LH on leydig cells. Secreted by the pituitary gland.
Testosterone  Maintains sperm production. Secreted by leydig cells in the testis.
Estradiol  Controls the synthesis of LH. It is formed by metabolizing testosterone in liver, muscle and adipose tissue. 20 – 25% is secreted from leydig cells.
Inhibin  It is secreted from Sertoli cells that inhibit the release of FSH.
Activin  Increases the release of FSH. It is secreted from Leydig cells.

Treatment of Male Infertility

Intrauterine Insemination (Vaccination)

Intrauterine Insemination, also known as vaccination, is one of the most common treatments for childless couples. It is applied to patients whose sperm count, structure and motility are below normal. Before the vaccination treatment is applied, the semen sample taken from the man is examined in detail in terms of number, movement, structure and antisperm antibodies. The female partner should be evaluated to see if her tubes are open. Before the procedure, the female partner may use medication to stimulate her ovaries. This increases the possibility of multiple pregnancy. During the time the woman is taking the medication, ultasonographic examinations are performed to monitor the development of the egg and when the diameter of the sac called follicle in which the egg is located reaches 18 to 20 mm, HCG injection (an injection that allows the follicle to rupture) is given. Vaccination is performed 34-38 hours after the HCG injection.

The semen taken from the man on the day of the procedure is prepared with special methods and enriched with sperm with good motility and structure. It is inconvenient to use semen without preparation during vaccination. This may cause allergic reactions, infections and pain in the woman. The prepared sample is introduced into the uterus of the expectant mother through a special catheter. Success is higher in women who menstruate regularly, have open tubes, do not have endometriosis and are under the age of 35. The chance of pregnancy with vaccination is 15-20% in each application.

In Vitro Fertilization

IVF treatment is the fertilization of the ovaries with sperm from the male partner outside the body and the transfer of the resulting embryos into the uterus of the expectant mother.

Steps of IVF treatment

IVF consists of four steps;

The development of eggs: hormone medication is used to stimulate the ovaries and allow a large number of eggs to mature. When the ovaries develop a large number of eggs, a large number of embryos can be obtained.

Egg collection; Egg collection is performed vaginally with a needle inserted into the ultrasound probe. There is no need for general anesthesia in this procedure, the expectant mother is given painkillers and local anesthesia.

Fertilization of eggs in the laboratory; the collected eggs are placed in enriched nutrient media. The sperm sample taken from the male partner is prepared with special methods and added to the eggs. The amount of sperm to be added is determined as 100,000 motile sperm per egg. The eggs stored in devices called incubators, which provide an environment similar to the mother’s body, are checked the next day to see if they are fertilized.

Transfer of embryos to the uterus of the expectant mother; Fertilized eggs, called embryos, are transferred to the uterus of the expectant mother 2 or 3 days after egg collection. During this period, embryos usually have 4-8 cells. Embryos are transferred to the uterus with a thin tube called a transfer catheter specially produced for this procedure. Embryo transfer is a very simple and painless procedure for the expectant mother. The embryos are placed in the catheter and after the cervix has been cleaned, they are placed into the uterus vaginally, usually under the guidance of abdominal ultrasonography. The number of embryos to be transferred is determined according to the age of the expectant mother and the quality of the embryos obtained. After the embryo transfer, progesterone hormone is used to support the expected pregnancy. On the tenth day after the transfer, the level of B-HCG hormone in the blood is determined to determine whether the pregnancy has occurred. Two weeks after the pregnancy is detected in the blood, the gestational sac is seen by ultrasonographic examination.

Microinjection

In microinjection, also called intracytoplasmic sperm injection (ICSI), a single selected sperm cell is injected into an egg. Before this, various chemicals are used to clean the cells around the egg. Microinjection is performed with the help of micropipettes attached to special microscopes. Since 1992, fertilization rates have reached 80-90% with the ICSI procedure. The preparation for microinjection and the steps after microinjection are the same as for IVF treatment.

Microinjection Therapy

  • Severe cases of male infertility;
  • Having few sperm in semen,
  • Low sperm motility,
  • Having less sperm of normal quality,
  • In cases where sperm cannot fertilize the egg despite having a normal number of sperm, microinjection treatment is applied.

Cases of azoospermia;

With this method, sperm obtained from men who have no sperm in their semen through MESA and TESE procedures are injected into the eggs taken from their wives, making it possible for these couples to have healthy children.

MESA and TESE Applications

In cases where there are no sperm cells in semen, sperm cells can be obtained from reproductive blood or testicular tissue (ovaries) and microinjection can be performed. These procedures are performed under local anesthesia and take approximately 30-60 minutes. These procedures have no negative impact on male sexual health. Male patients enrolled in this program are evaluated by a urologist and informed about the procedure. In addition to cases where there is no sperm in the semen, they can be candidates for these procedures in cases where there is no sperm in the semen in normal structure or all of the sperm found in the semen are dead. MESA and TESE are the treatment methods of choice in cases of severe male infertility with dead or no live sperm in the semen.

MESA process

The MESA procedure is applied to men with blocked ducts. Sperm is obtained from these patients with microsurgery. MESA procedure is performed under local anesthesia.

TESE procedure

With this procedure performed under local anesthesia, small pieces of tissue are taken from different parts of the testicle. These pieces are separated by special methods and microinjection is performed with the sperm cells obtained. TESE procedure can be applied in the treatment of cases with no sperm in the semen, as well as cases with no normal or live sperm in the semen.

Sperm cells obtained by MESA and TESE procedures are prepared in the laboratory. Dormant spermatozoa are given motility with chemicals that accelerate intracellular metabolism, making it possible to use live spermatozoa in microinjection. Also immature. Sperm cells are matured in the laboratory in enriched media and incubators before microinjection.

No increase in anomalies has been detected in babies born from pregnancies obtained after microinjection applications using sperm obtained through MESA and TESE procedures.

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Male Infertility and Its Solutions