In-vitro Fertilization (IVF)
She has been working as a gynecologist and obstetrician at Anadolu Medical Center since 2007.
In-vitro fertilization was performed in 1973 for the first time, but pregnancy did not develop with the embryo obtained. In July 1978, "Louise Brown", the world’s first test-tube baby, was born in UK. Thereafter, hormone drugs have been developed for use in ovulation therapies. But the real progress was made with the invention of ICSI (micro-injection) in 1996. Therefore, the rate of success in in-vitro fertilization applications has increased, and a significant distance has been covered in male infertility problems.
In her period of life, an adult female produces one egg cell every month until the menopause period. In most of the infertility therapies, the number of egg cells is increased in order to produce numerous embryos. This is achieved by short-term use of various hormone medications. More eggs will increase the chance of fertilization and developing more quality embryos, and allow transferring the most quality embryo to the mother.
Unlike the egg cell which is the only one produced in a month, there are millions of sperms, the male reproductive cell. The process of formation of a sperm in the male reproductive organs is approximately 75 days. At the end of this period, sperms that become mature are ejaculated in semen. Under normal conditions, sperm cells compete for a single egg and the fastest and the most quality one among them penetrates the outer membrane and realizes fertilization.
16-20 hours after the sperm enters the egg cell, 2 "pronuclei", which are the signs of fertilization, appear. One of the pronuclei contains the genetic materials, i.e. chromosomes, belonging to the mother, and the other contains chromosomes of the father. As hours pass, these two combine and form the chromosomes of the baby.
Infertility is one of the most common and important problems of today’s society. 10-15 percent of the couples in the fertility age encounter some challenges in having a child, and can only have a child with treatment.
In general, we can speak of infertility when a healthy woman under 35 is not pregnant after regular sex without protection for a year. Age factor is closely related to infertility. As a woman gets older, especially when she is over 35, there is a significant reduction in fertility. For this reason, this 1-year period can be shortened in order to diagnose fertility in women over 35.
Infertility may stem from the female or the male, or both. While 30 percent of infertility cases are due to insufficient number and quality of sperms in men, 30 percent of the cases are due to female infertility. In 20 percent of the infertility cases, both the female and the male are the source of the problem. In the remaining 20 percent group, all examinations are normal, and there is no reason for infertility. We call this “unexplained infertility".
One out of every 7-10 couples experience infertility. Only in US there are 10 million couples who have an infertility problem, and in Turkey the number of couples who have an infertility problem is about 2-3 million.
There are approximately 1 million tube babies born in the world until this date. Although not definitive, it is estimated that there are 15 thousand tube babies in Turkey.
About 1 percent of the male population has azoospermia (lack of sperm in semen). Azoospermia is the cause of not having a child in 10 percent of men who have infertility. There are two types of azoospermia. The condition which is characterized by no sperm production in the testicle is called non-obstructive azoospermia. Here there is a further distinction. There may be conditions in which no sperm production occurs in the testicle, whereas there are conditions in which small tubules which produce sperms exist, but no sperms can be ejaculated. The condition in which sperms are produced by cannot be ejaculated due to duct obstruction is called obstructive azoospermia. In the TESA (Testicular Sperm Aspiration) method which is applied to patients with obstructive azoospermia, a needle is locally inserted into the testicle and sperms are collected. In this method, the chance to find a sperm is close to 100 percent. If as a result of testicle examination and hormone test non-obstructive azoospermia is identified, Micro-TESE (Testicular Sperm Extraction) method is applied. Tubules under the testicle are examined under a microscope. Since tubules in the sperm are different, they are differentiated and sperms are extracted. The chance to collect sperms with this method is nearly 52-53 percent.
When a baby girl is born, she has nearly 400,000 eggs.
A healthy male releases 300 – 500 million sperms to the vagina in each ejaculation.
Ovulation problems are the most common cause of female infertility. Polycystic ovary syndrome is the primary reason of ovulation irregularity in women. Polycystic ovary syndrome (PCOS) which is one of the most common reasons of infertility alongside menstrual irregularity and which is caused by ovarian cysts may also be accompanied by hirsutism and weight gain. Apart from that, the excess of prolactin, a hormone which is secreted by the pituitary gland in the brain and normally promotes lactation has also a negative effect on ovulation. In such a case, prolactin secretion is reduced by medication therapy and the woman may again ovulate regularly.
Similarly when the woman’s thyroid gland functions are insufficient, ovulation can be restored by thyroid hormone replacement therapy. Excessive exercising or dieting by the woman is another factor which may suppress ovulation and cause menstrual irregularity.
In general, ovulation problems are attempted to be corrected by medication therapy.
This is another common problem observed in women. Causes like reproductive organ infection, ectopic pregnancy, appendicitis endometriosis (the lining of uterus growing outside of the uterine cavity) may give rise to adherence and obstruction in fallopian tubes. When obstruction develops, a mechanical obstacle occurs which prevents the combination of the egg and the sperm, and pregnancy does not develop. Such obstructions may sometimes be corrected by surgery. However, in severely damaged tubes, the success rate is significantly low, and re-obstruction possibility is high. In this case, in-vitro fertilization is performed.
Such structural abnormalities may be congenital or may later develop due to myomas. Formation of an excess septum due to a congenital curtain in the middle of the uterus is an example for this kind of malformation. Another problem that later develops and causes intrauterine irregularity is myomas or polyps. All these prevent the fertilized egg from adhering to the uterine wall and growing properly, and may cause infertility.
Since sperm production is under the control of FSH and LH hormones secreted from the pituitary gland in the brain, irregular secretion of these hormones may lead to infertility.
Testicles normally descend down to the scrotum at birth or in 1 year. Healthy sperm production takes place at a temperature lower than body temperature. If testicles do not descend down, the testicles that are not descended are subject to high temperature, and as a result sperm production is deteriorated and male infertility may arise.
Drugs and radiation therapy administered during tumor treatment have an adverse effect on sperm production.
Testicular trauma represents a cause of infertility subject to injuries and accidents.
Varicocele is the abnormal enlargement of the veins around the testicles. It is not always the case that every man with varicocele is infertile, but varicocele is among the causes of infertility. In a research, it was determined that 20 percent of men who had impregnated their wives in the past had varicocele. The prevalence of varicocele in infertile couple where the woman is fertile is around 35-40 percent.
Varicocele is more frequently seen on the left side. Observed in 10 percent of men, this condition does not generally give rise to any complaint. Varicocele is determined by testicular examination and ultrasound examination. In men with varicocele, elevated temperature in the scrotum subject to slowed blood flow may lead to infertility. In varicocele surgery, enlarged veins are treated by injecting special solutions or embolization. Surgical intervention is recommended when any other cause of infertility is not detected or varicocele causes pain.
Microbial infections in reproductive organs may cause infertility. For example, we can list tuberculosis, sexually transmitted diseases (chlamydia), gonorrhea.
Genetic diseases like Klinefelter syndrome and cystic fibrosis are also among the causes of infertility.
The man’s profession, smoking, narcotics and drugs used in the treatment of certain diseases may also give rise to infertility.
Couples who apply to our IVF center to have a child, a treatment of the cause is first recommended. If unexplained infertility exists, general treatments that aid reproduction can be applied. These treatments are as follows:
Ultrasound examinations of the patient are performed on the 2nd or 3rd day of menstruation. If the ultrasound shows that there are no obstacles to start treatment in the uterine or ovaries, oral medications are given to the patient to induce ovulation. In this period of time, ultrasound follow up is performed at certain intervals.
This method is employed in case of mild deformities related to sperm quantity, motility, and shape, problems in the cervical mucus (spermicidal antibodies), or inability to have sexual intercourse, and unexplained infertility. With this method, the woman's eggs are stimulated by hormones, and the time of the procedure is determined according to growth of eggs. A sperm sample collected from the man is put through special laboratory procedures to determine quality and motility. Healthy sperms with high motility are separated for use in procedures. The prepared sperm is administered to the woman’s womb with the help of a special cannula in examination position, and after the procedure, the patient is let to rest for half an hour in lying position. The success rate of this procedure varies from person to person.
In this method, eggs induced via hormones are monitored for growth at certain intervals using ultrasonography. When egg sacs called follicles reach a certain size, preparations are made for egg collection. Egg Collection Procedure takes place at 35th - 36th hour after the Trigger Shot which plays a role in the maturation of eggs. Eggs obtained are collected in special solutions under laboratory conditions. They are kept in cabins (incubators) containing a gas mixture suitable for the embryo at a body temperature of 37 degrees. These incubators which have a humid and dark environment stimulate the uterus. On the other hand, sperms collected from the husband are processed and prepared at the laboratory.
After the preparation procedures, eggs and sperms are incubated together under a microscope for fertilization to take place. There should be 50,000 - 100,000 sperms around each egg. Eggs are followed up for fertilization the day after the procedure, and for division in the subsequent days, and all information are entered in the patient record.
At a suitable time determined by embryologists and gynecologists, embryos with the highest quality (on the second, third, fourth or fifth day after the procedure) are selected. A suitable number of embryos are implanted in the uterus with the help of a thin cannula. The number of embryos to be transferred varies according to maternal age, the quality of embryos and previous trials. In normal applications, this number is limited to maximum three embryos.
This method is used when sperm count, motility, and number of sperms in normal structure are low, or despite normal sperm count, sperms are unable to fertilize the egg. It should be ascertained in advance whether the eggs to be used in microinjection procedure are mature or not. A sperm that exhibits a proper structure is selected with high magnification under a microscope and is injected into the egg. In a single procedure, a single egg is fertilized with a single sperm. As in IVF application, fertilization is checked the next day, and division the subsequent days. The best quality and suitable number of embryos are implanted in the uterus.
Fertilized egg
16-20 hours after the sperm enters the egg cell, 2 "pronuclei", which are the signs of fertilization, appear. One of the pronuclei contains the genetic materials, i.e. chromosomes, belonging to the mother, and the other contains chromosomes of the father. As hours pass, these two combine and form the chromosomes of the baby.
Two-cell, four-cell, eight-cell
The embryo is divided into 2 cells about 26 hours later. It divides into 4 cells the next day, and 8 cells the third day.
Fifth-day embryo
In the fourth-day embryo it is not possible to differentiate the number of cells with the embryo, and the fifth-day embryo resembles a balloon filled with water, and is named blastocyst.
Sixth-day embryo
Implantation occurs when the embryo exits the membrane surrounding it and adheres to the wall of the uterus.
Lack of sperms in semen is called azoospermia. This condition is characterized by ejaculatory duct obstruction or sperm production disorder in the testicles. The treatment method is microinjection. In this treatment method, sperms are collected via a surgical procedure called TESA or TESE by a urologist. About 5 percent of the couples who apply to IVF centers today are treated using this method.
TESA (Testicular Sperm Aspiration)
In case of lack of sperms in the semen obtained from the male due to obstruction or non-development of ejaculatory ducts, or very low sperm production, this method is used to withdraw fluid from testicles using a needle and to collect sperm cells.
The operation is performed under local anesthesia, and the patient can resume normal living activities the same day. Mature or developing sperms obtained via this method are used in ICSI (microinjection) method.
TESE (Testicular Sperm Extraction)
When TESA method is not successful or in case of severe sperm production insufficiency, this method is used to extract a piece from testicles by surgery. The operation is performed under local anesthesia, and the patient can resume normal living activities the same day. In this procedure, the testicles are examined under a surgical microscope and small pieces of tissue are extracted. Use of a surgical microscope enables to differentiate easily those sites of tissue where the possibility of sperm presence is higher. At the same time, damage to veins that supply the tissue is minimized. Pieces of tissue extracted are subject to further examination under a microscope. When a sperm cell is found, it is put through various preparation stages for use in ICSI (microinjection) method.
Micro Tese Method
Azoospermic males who cannot have a child can have a child with a method called “micro tese ", i.e. “microscopic testicular sperm extraction”. In cases not associated with obstruction, there is either no sperm production in the testicles, or there is very limited production in certain sites. While there is no production in some tubules, there may be a small number of sperms in others. In this procedure where sperms are collected from the testicles of men who have no sperm in their semen under a surgical microscope, areas where sperms are found can be identified much easily, and sperms collected. Testicles are opened under anesthesia and are examined under a microscope. In this method, testicular sites where sperms are produced are selected better, and because the amount of tissue collected is smaller, pieces can be collected from several sites. These tissues are cut by the embryologist at the laboratory, and sperm cells spilt or adhered to the channels are separated, and used in the microinjection procedure.
This method raises the chance to find sperms under microscope examination and enables to obtain more sperms. More importantly, loss of testicular tissue is less compared with the old method. Therefore, testicles suffer less damage during the operation, and procedures likely to reduce blood levels of secreted testosterone are avoided.
Assisted Hatching
Implantation occurs when the embryo exits the membrane surrounding it and adheres to the wall of the uterus. When the layer surrounding the embryo is thick and the maternal age is advanced, adherence becomes difficult, and even impossible. Assisted hatching is based on thinning this layer down under a microscope.
Blastocyt Transfer
This method can be applied if minimum 5 very quality embryos have been obtained in the first three days after fertilization. Conducted on the fifth day after the egg collection process, this transfer is useful in selecting the best embryos. This method is also appropriate for preventing multiple pregnancies to the extent possible.
Embryo Cryopreservation
Embryos of the best quality and of the necessary number are transferred to the woman. The remaining embryos of good quality can be kept for cryopreservation. If pregnancy is not achieved after the first transfer or a second child is desired, embryos can be thawed and implanted into the uterus.
With this procedure, there is no need to induce ovulation by medications and to collect eggs. Embryos are placed in various solutions at certain time intervals and at certain temperatures and gain resistances to cold. Thereafter, they are placed in an embryo freezing device. Embryos may be kept for 5 years due to legal limitations.
In vitro maturation
This is a method where eggs are matured outside the body. It is particularly preferred in women who overrespond or never respond to ovulation stimulating drugs. Eggs are collected without drug induction and are matured in the laboratory environment.
Preimplantation genetic diagnosis (PGD)
There are several tests that are used to examine whether the chromosomal structure of the baby, i.e. its genetic material, is healthy or not, also there are some screening tests used during the pregnancy process (double and triple tests) and examinations of cells sampled from the amniotic sac (amniocenthesis).
Preimplantation genetic diagnosis, i.e. genetic examination of the embryo prior to the transfer to the mother is a very important diagnostic method for couples who carry genetic diseases or have a child with a genetic disease. PGD is recommended in case of recurrent miscarriages, advanced maternal age, and several unsuccessful IVF trials. Couples can have a healthy child via this method that excludes genetic diseases.
How is preimplantation genetic diagnosis (PGD) applied?
After evaluating whether the patient is suitable for PGD or not, genetic defects are investigated in blood collected from the patient or the carriers. To this end, the mother is prepared for the IVF treatment. Eggs collected are fertilized by the sperms of the father-to-be. When embryos reach the third day (8-cell embryo), 1 or 2 cells (blastomers) are collected under a microscope. Following this procedure which is called blastomer biopsy, cells are sent to the genetic diagnosis laboratory. After various procedures, embryos that carry the disease and the ones that are healthy are identified. Embryos that do not carry the disease are transferred to the uterus.
Although PGD has developed as fast as genetics as a side branch, its use in every embryo has not yet been accepted. The generally accepted practice in international medicine is to use the method in cases of increased risk of chromosomal disorder such as known familial anomaly, a chromosomal disorder in previous babies, or recurrent miscarriages, or advanced maternal age.
Another advantage of this method which is applied under a microscope is the ability to make an incision without damage to the testicular blood vessels.
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