General Informations

The IVF-ICSI Cycle

Homapage / The IVF-ICSI Cycle

The IVF-ICSI (In Vitro Fertilization- Intracytoplasmic Sperm Injection) Cycle

The IVF-ICSI (In Vitro Fertilization- Intracytoplasmic Sperm Injection) Cycle

Ovarian Stimulation

Controlled ovarian stimulation begins on the second or third day of your menstrual cycle (the second or third day of your period) and takes around seven to ten days.

  • A nurse advises you on how and when to use your medication, which you should keep in the refrigerator. 
  • You visit the unit between 8.30 a.m. and 10.30 a.m. for blood tests, ultrasound monitioring and E2 measurements.
  • Throughout the ovarian stimulation phase,  the unit  will telephone you each afternoon to tell you your medication dosage and the time of your next appointment. It is important that you follow these instructions and do not inject medication without this confirmation.
  • “Please avoid doing any injections before coming to your next visit.”
  • On approximately the tenth day of your menstrual cycle, the medication that stimulates the final   maturation of the oocyte is given.

Which drugs are used during treatment?

There are several group of drugs used in the IVF-ICSI treatment. These are: 

1. Drugs used to stimulate the growth of the follicle; 

A.  Gonadotrophines

   a. Luteinizing hormone (LH)

   b. Follicle-stimulating hormone (FSH)

B. Letrozole

C. Clomiphene citrate

2. Drugs used to prevent premature rupture of the follicle;

A.  Gonadotrophine-releasing hormone (GnRH) agonist                                      

B. GnRH antagonist

3. Drugs used for the final maturation of the egg; 

A. hCG 

B. GnRH agonist

4. Drugs used to support endometrium, the inner linning of the uterus;

A. Progesteron preparations-vaginal gel, intramuscular injection

B. Estrogen preparations-oral, transdermal

5. Others;            

In the ovaries, the eggs are placed in the follicles.  This  is  a  fluid  filled  structure  in which  the  egg (oocyte) developed. Follicles  contains cells (granulosa cells)  which  produce  the  female  hormone  (estrogen). In the natural cycle, only one egg is selected and grow. When the optimal growth is achieved  an acute rise of LH ("LH surge") triggers final maturation of the egg, rupture of the follicle and support  the endometrium. But in IVF treatment we want to get more than one egg. So, stimulatory drugs are used to enhance multifolicular development. Growing eggs may have the potential to rupture spontaneously before our pick up. In order to prevent spontaneous ovulation, suppressory drugs must be used. When optimal follicular growth is obtained, final maturation of the egg can be achieved by luteinizing hormone (LH) containing drugs. After embryo transfer we use mainly progesterone preparations to support the inner layer of the uterus.

1. Drugs used to stimulate the growth of the follicle;

A. Gonadotrophines: These include the follicle-stimulating hormone (FSH), luteinizing hormone (LH). These hormones regulate normal growth, sexual development and reproductive function. FSH and LH act together in the follicular growth.

   a) Luteinizing hormone (LH): Triggers final maturation of the egg, rupture of the follicle and support the endometrium.

   b) Follicle-stimulating hormone (FSH) : Regulates the early development of the ovarian follicles. 

These groups of drugs are used in all treatment protocols. Two kinds of gonadotrophines preparations are available; preparations containing both LH and FSH; that is human menauposal gonadotrophine (HMG) and FSH only. 

Although hMG preparations are effective and safe, being a purified urinary product, it may cause local side effects like pain and allergic reactions more than a recombinant product. 

FSH preparations can be produced either by recombinant technology or by purification of hMG. Recombinant preparations are preferred because side effects are lower..

Selection of the type of the drug depends on the patient situation. Generally if there is previous poor response to FSH alone, in hypo gonadotropic amenorrhea or if too much suppression is observed we use hMG. hMG can be used alone or combined with FSH.

B. Letrozole: It increases the response of the ovary to the stimulatory drugs and in turn decreases the total used gonadotrophine. By using letrozole the stimulation can be carried out with more physiological, lower estrogen blood levels. 

C. Clomiphene citrate (CC): It enhances the release of  endogeneous gonadotrophines. This results in selection of the follicles. At the end by sensitizing the ovary to the stimulation, CC decreases the amount of totally used stimulatory drug.

2. Second group are the drugs used to prevent premature rupture of the follicle. These are:

A. GnRH agonists: GnRH agonist drugs resemble and so replace GnRH. By this way after a first increase, it then suppresses the gonadotrophine secretion. By blocking normal physiology , uncontrolled LH surge which may result in early follicular rupture may be prevented. This enables us to control the cycle.

B. Gonadotrophine antagonists: These are the other alternative group of drugs used to prevent early ovulation. These are a class of compounds that compete with natural GnRH, thus decreases or blocks GnRH action in the body.

3. Drugs used for the final maturationof the egg; that is the drugs resembling to LH: 

There are two group of drugs. Generally human chorionic gonadotrophine (hCG) is used for the final maturation of the egg in the growing follicle. But in some polycystic ovarian patients if the response is too high, we may prefer analogs in order to prevent severe Ovarian Hyper stimulation Syndrome (OHSS).

4. Drugs used to support endometrium, the inner linning of the uterus:

Finally, the endometrium, the inner layer of the uterus that accepts the embryos is supported by progesterone and/or estrogen preparations.

5. Others: 

Folic acid preparations are used to prevent some spinal cord malformations. It is offered 3 months before getting pregnant

Protocols Used in Our Clinic During IVF-ICSI Cycle ?

There are several

1. Short-Antagonist Protocols:

A.  Gonadotrophine+Antagonist Protocol:

Being a patient friendly protocol, the short antagonist protocol is used in the majority of cases at our clinic. Its usage is easy, less stimulatory drugs are needed, side effects are low.

The steps of this protocol are

  1. The stimulation of the patient’s ovarian follicles using stimulatory drugs begins on the second or third day of her menstrual cycle. Antimullerian hormone(AMH), basal antral follicle count in the ultrasound and estrogen, LH and progesterone hormone levels are obtained to determine the appropriate dose of the stimulatory drugs. 
  2. After this basal evaluation, monitoring of the hormones and ultrasound measurements are necessary during ovarian stimulation  to adjust the stimulatory drug dose and timing of the antagonist drugs. 
  3. When the optimal growth of the follicles are obtained; that is the follicle size 18-19mm, Human chorionic gonadotrophin (hCG) which is the drug that stimulates the final maturation of the oocyte is given. 
  4. 36 hours later, oocyte pick up (OPU) is carried out. As soon as sedation anesthesia. is given the patient feels no pain duing this procedure, but after pick up you may feel little uncomfort. Sperm is collected on the same day as OPU. Before this, three to four days of sexual abstinence is needed for optimal sperm count and motility. 
  5. In cases of azoospermia, sperm is collected by extraction from the testicles. 
  6. Intracytoplasmic sperm injection (ICSI) or invitrofertilization (IVF) is performed on the OPU day.  The resulting embryos are cultured in special mediums and kept in special incubators until the transfer time. Transfer takes place three to five days after OPU. Transfer time and number depends on embryo quality, women’s age and patient’s past failed IVF cycles and infertility duration. 

The time from the starting of the ovulation induction to embryo transfer is usually fourteen to seventeen days.

 

B. Letrozole + Gonadotrophine + Antagonist Protocol:

Letrozole increases the response of the ovary to the stimulatory drugs and in turn decreases the total used gonadotrophine. By using letrozole the stimulation can be carried out with more physiological, lower estrogen blood levels. This protocol is generally preferred in the low ovarian reserve patients having a past history of poor IVF outcome with other protocols or in cancer especially breast cancer patients. 

The steps of this protocol are

  1. After monitoring Antimullerian hormone(AMH), basal antral follicle count in the ultrasound and estrogen, LH and progesterone hormone levels, letrozole is started on the second or third day of the menstrual cycle and continued for five days.
  2. Stimulatory drugs are used either at the same day or 2 days later depending on patients condition. If it is thought to get too low response, then both letrozole and gonadotrophines are started at the same day.  
  3. After this basal evaluation, during ovarian stimulation, monitoring of the hormones and ultrasound measurements are necessary to adjust the stimulatory drug dose and timing of the antagonist drugs. 
  4. When the optimal growth of the follicles are obtained;that is 18-19mm, Human chorionic gonadotrophin (hCG) which is the drug that stimulates the final maturation of the oocyte is given. 
  5. 36 hours later, oocyte pick up (OPU) is carried out while the patient is under sedation anesthesia. This procedure is painless, but after pick up you may feel little uncomfort. Sperm is collected on the same day as OPU. Before this, three to four days of sexual abstinence is needed for optimal sperm count and motility. In cases of azoospermia, sperm is collected by extraction from the testicles. 
  6. Intracytoplasmic sperm injection (ICSI) or invitrofertilization (IVF) is performed on OPU day. 
  7. The resulting embryos are cultured in special mediums and kept in special incubators until the transfer time. Transfer takes place three to five days after OPU. Transfer time and number depends on embryo quality, women’s age and patient’s past failed IVF cycles and infertility duration. 
 

C. Clomiphene citrate (CC) +  Gonadotrophine+Antagonist Protocol:

This resembles to the letrozol protocol. This is preferred in the low ovarian reserve patients. CC decreases the total amount of stimulatory drugs by sensitizing the ovary to the stimulation. 

The steps of this protocol are

  1. After monitoring Antimullerian hormone(AMH), basal antral follicle count in the ultrasound and estrogen, LH and progesterone hormone levels, CC is started on the second or third day of the menstrual cycle and continued for five days.
  2. Stimulatory drugs are used 2 days later.
  3. After this basal evaluation, during ovarian stimulation, monitoring of the hormones and ultrasound measurements are necessary to adjust the stimulatory drug dose and timing of the antagonist drugs. 
  4. When the optimal growth of the follicles are obtained;that is 18-19mm, Human chorionic gonadotrophin (hCG) which is the drug that stimulates the final maturation of the oocyte is given. 
  5. 36 hours later, oocyte pick up (OPU) is carried out while the patient is under sedation anesthesia. This procedure is painless, but after pick up you may feel little uncomfort. Sperm is collected on the same day as OPU. Before this, three to four days of sexual abstinence is needed for optimal sperm count and motility.  In cases of azoospermia, sperm is collected by extraction from the testicles. 
  6. Intracytoplasmic sperm injection (ICSI) or invitrofertilization (IVF) is performed on OPU day. 
  7. The resulting embryos are cultured in special mediums and kept in special incubators until the transfer time. Transfer takes place three to five days after OPU. Transfer time and number depends on embryo quality, women’s age and patient’s past failed IVF cycles and infertility duration. 
 

2. Agonist Protocols:

A. Long- Agonist Protocol:

A patient’s ovaries can also be prepeared for an IVF cycle using a long protocol. 

The steps of this protocol are

  1. 1. Pretreatment with suppressor agonist drugs is used to control follicle growth and prevent premature rupture. They block the normal physiology and enables us to control the cycle.  Agonists are started on the 21stday of the previous menstrual cycle and continued until hCG day.  
  2. 2. Stimulatory drugs are started on the second or third day of the menstrual cycle after monitoring Antimullerian hormone(AMH), basal antral follicle count in the ultrasound and estrogen, LH and progesterone hormone levels,
  3. 3. After this basal evaluation, during ovarian stimulation, monitoring of the hormones and ultrasound measurements are necessary to adjust the stimulatory drug dose. 
  4. 4. When the optimal growth of the follicles are obtained;that is 18-19mm, Human chorionic gonadotrophin (hCG) which is the drug that stimulates the final maturation of the oocyte is given. 
  5. 5. 36 hours later, oocyte pick up (OPU) is carried out while the patient is under sedation anesthesia. This procedure is painless, but after pick up you may feel little uncomfort. Sperm is collected on the same day as OPU. Before this, three to four days of sexual abstinence is needed for optimal sperm count and motility. In cases of azoospermia, sperm is collected by extraction from the testicles. 
  6. 6. Intracytoplasmic sperm injection (ICSI) or invitrofertilization (IVF) is performed on OPU day. 

The resulting embryos are cultured in special mediums and kept in special incubators until the transfer time. Transfer takes place three to five days after OPU. Transfer time and number depends on embryo quality, women’s age and patient’s past failed IVF cycles and infertility duration

 

B. Long Stop Protocol:

The steps of this protocol are

  1. Pretreatment with suppressor agonist drugs is needed to control the follicular growth and prevent premature rupture.  Agonists are started on the 21st day of the previous menstrual cycle.  
  2. Stimulatory drugs are started on the second or third day of the menstrual cycle after  monitoring Antimullerian hormone(AMH), basal antral follicle count in the ultrasound and estrogen, LH and progesterone hormone levels,
  3. After this basal evaluation, during ovarian stimulation, monitoring of the hormones and ultrasound measurements are necessary to adjust the stimulatory drug dose and timing of the antagonist drugs. 
  4. When the optimal growth of the follicles are obtained;that is 18-19mm, Human chorionic gonadotrophin (hCG) which is the drug that stimulates the final maturation of the oocyte is given. 
  5. 36 hours later, oocyte pick up (OPU) is carried out while the patient is under sedation anesthesia. This procedure is painless, but after pick up you may feel little uncomfort. Sperm is collected on the same day as OPU. Before this, three to four days of sexual abstinence is needed for optimal sperm count and motility.  In cases of azoospermia, sperm is collected by extraction from the testicles. 
  6. Intracytoplasmic sperm injection (ICSI) or invitrofertilization (IVF) is performed on OPU day. 
  7. The resulting embryos are cultured in special mediums and kept in special incubators until the transfer time. Transfer takes place three to five days after OPU. Transfer time and number depends on embryo quality, women’s age and patient’s past failed IVF cycles and infertility duration
 

3.Luteal phase supressıon protocol:

The steps of this protocol are

  1. Estrogene tts band is applied on the 21st and 23rd day of the previous menstrual cycle.  
  2. GnRH antagonists are started on the 22nd day of the previous menstrual cycle and continued for three days. 
  3. Stimulatory drugs are started on the second or third day of the menstrual cycle after monitoring Antimullerian hormone(AMH), basal antral follicle count in the ultrasound and estrogen, LH and progesterone hormone levels,
  4. After this basal evaluation, during ovarian stimulation, monitoring of the hormones and ultrasound measurements are necessary to adjust the stimulatory drug dose and timing of the antagonist drugs. 
  5. When the optimal growth of the follicles are obtained;that is 18-19mm, Human chorionic gonadotrophin (hCG) which is the drug that stimulates the final maturation of the oocyte is given. 
  6. 36 hours later, oocyte pick up (OPU) is carried out while the patient is under sedation anesthesia. This procedure is painless, but after pick up you may feel little uncomfort. Sperm is collected on the same day as OPU. Before this, three to four days of sexual abstinence is needed for optimal sperm count and motility.  In cases of azoospermia, sperm is collected by extraction from the testicles. 
  7. Intracytoplasmic sperm injection (ICSI) or invitrofertilization (IVF) is performed on OPU day. 
  8. The resulting embryos are cultured in special mediums and kept in special incubators until the transfer time. Transfer takes place three to five days after OPU. Transfer time and number depends on embryo quality, women’s age and patient’s past failed IVF cycles and infertility duration
 

Other Drugs:

In all protocols, a progesterone medication is prescribed to support the endometrium and increase the chance of pregnancy. It is started the day after OPU. Progesterone can be administered vaginally or by intramuscular injection depending upon the clinic. After a positive pregnancy test, the patient will continue with vaginally administered progesterone until the 12th week of gestation. There is no difference between the two routes of administration.

How is it decided which protocol to use?

In our clinic short protocols are used for more than ninety percent of patients. Short protocols are patient-friendly because fewer injections are needed. Furthermore, a lower dose of gonadotrophine may be enough to stimulate the ovaries, which in turn decreases the cost. In addition, the short protocol lowers the risk of hyper stimulation syndrome. With all these advantages, the antagonist protocol is preferred in our clinic. Despite these, asynchronous follicular development is the major unwanted condition that may frequently be seen in these cycles. Because of this synchronicity, mature oocyte number can be lower than the expected. By using long protocols, more synchronous follicular development can be achieved. Higher suppression of the ovaries seen in the long protocols increases the amount of gonadotrophine used and more injections are needed.  Long protocols are not suitable in patients with poor ovarian reserve. In order to get more mature oocyte, we prefer long protocols in patients when genetic screening is needed. Additionally in patients with previous asynchronous development, long protocols may be used.

Are all patients given the same amount of drugs? If not, how is the dosage determined?

The protocol and dose of the drugs are always individualized. The stimulatory drug dose is determined according to the woman’s age, weight and, if she has received treatment before, the previous response of her ovaries to gonadotrophines.

What side effects do high dose treatments have?

Side effects are uncommon. Occasionally, sensitivity and redness may develop in the injection area.  

The most unwanted side effects of this treatement is Ovarian hyper stimulation syndrome (OHSS)

What Is OHSS?

Ovarian hyper stimulation syndrome  (OHSS) is a condition which may develop as a result of stimulatory treatment in polycystic ovarian patients who have large number of eggs in their ovaries. Although early OHSS can occur three to seven days after hCG, it can also be seen lately, twelve to seventeen days after hCG. In mild cases, there may be abdominal discomfort, weight gain, an increase in abdominal circumference and enlarged ovaries. However in more severe cases, there may be nausea, vomiting, diarrhea and fluid collection in the abdomen or chest. In rare cases, it may be complicated with difficulty in breathing, decreased urine output, hypotension, generalized edema, and impaired liver and renal function. In addition, there may be an increased risk of thrombosis. To confirm the diagnosis some blood tests (estradiol measurements and complete blood count) are done.

Treatment depends upon the severity of the symptoms. In mild or moderate cases; rest, hydration and a protein-rich diet are recommended. For severe cases, hospitalization may be needed. Intravenous hydration given. Very rarely albumin and fluid extraction with a needle to relieve symptoms may be needed. Anticoagulant treatment can be started to prevent thrombosis. Abdominal circumference, weight gain and blood test results should be monitored. 

The syndrome generally lasts in ten to fourteen days, but if pregnancy occurs, it may continue for up to three weeks.

Oocyte Pick-Up (OPU)

  • Oocyte pick-up takes place thirty-six hours after HCG
  • You should fast (not eat or drink) after 24.00 the day before OPU .
  • OPU is performed under sedation and takes around twenty minutes. You can leave the hospital one or two hours later.
  • During this visit, you will be given information about the medication you should use after OPU.
  • On the same day as OPU, sperm is collected. Before this, three or four days of sexual abstinence is needed for optimal sperm count and motility.
  • The day after OPU, you can have the information about the fertilization of your embryos. 

General Information About Egg Pick Up:

Eggs are collected from the ovaries by a needle connected to a vaginal ultrasound probe. Sedation analgesia is used to prevent pain during the procedure. Some side effects of anesthesia such as nausea and vomiting may occur. There will be no drawbacks in taking 2-3 tablets of paracetamol to relieve the inguinal pain that may occur following the procedure. You will be given soft-fluid nutrients and permitted to leave the center about 2-3 hours. During this period nurses will check your blood pressure and pulse. There is a very small risk of bleeding and infection arising from the utilization of a needle during the collection of egg. You may be requested to apply the hospital for follow up. Very rarely blood transfusion or laparoscopy may be needed.

Refrain from jogging, skiing, aerobic or high impact activity after pick up.

 

Follicles sometimes rupture prematurely despite the usage of suppressor agonist or antagonist drugs. The risk is higher in the aged women with poor reserve, especially in unifollicular growth. Premature rupture occurs because of uncontrolled LH secretion in the body. Close monitoring is essential in this group of patients. Although frequent blood testing and ultrasound monitoring is done, there is still a risk of premature rupture. The risk can be assumed by the measuring LH and estradiol level. A threefold increase of LH compared with the basal level, and estradiol drop after HCG helps us in predicting uncontrolled LH peak and premature ovulation risk.

Embryo Transfer

  • Embryo transfer takes place three to five days after OPU, usually in the afternoon. The exact day and the number of embryos transferred depends on embryo quality, the woman’s age, the duration of infertility and any history of past failed IVF attempts.
  • The hospital will telephone and/or email you with the day and time of the transfer.
  • You should come to the hospital two hours before transfer time.
  • You do not need to fast.
  • Embryo transfer takes place in the same room as the retrieval.
  • Embryo transfer is not a painful procedure and does not usually require anaesthesia or sedation. Sometimes in vaginismus patients or in difficult transfers anesthesia may be required.
  • You need a full bladder for embryo transfer. This makes it easier for the doctor to insert the catheter and perform the transfer.  You should drink seven to eight glasses of water in the two hours before embryo transfer.
  • After embryo transfer, you spend some time resting in a recovery room, lying on your back.
  • You are discharged thirty minutes to one hour after the transfer.
  • Bed rest after embryo transfer does not increase the chance of pregnancy. However, we advise you to avoid high impact physical activity, for the first twenty-four hours. We also recommend that you avoid sports, demanding physical tasks and the lifting of heavy objects until the day of your pregnancy test.
  • Although there is no objection to car and air travel, we recommend that you do not fly on the day of the transfer, but wait until the next day.
  • Continue to take your prescribed medications until your pregnancy test. If you have vaginal bleeding it is better to stop taking coraspin.
  • Do not have sexual intercourse until you have the results of your pregnancy test.
 
Embryo transfer

Pregnancy Testing

  • Fourteen days after OPU, you should have a pregnancy blood test and let us know the results. Please do the test even if you have bleeding, because you may still be pregnant.
  • If the result if positive, repeat the test two days later, continue to use medications. If the test is doubled then three weeks after a positive pregnancy test, you should have an ultrasound scan.
  • If the result is negative, stop taking all medications and contact your doctor.
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