IVF Protocols

IVF Protocols

During an IVF cycle certain medications are used to superovulate the ovaries in order to produce numerous of eggs. These medications may be given in a variety of combinations called protocols.

In conventional IVF two types of protocols are commonly used; the long protocol and the short protocol. The drugs used in both protocols are the same; however the dosages and the period administered are different. The physician reviews the patient’s records (woman’s age, response to the medication and the outcome of previous attempts) and determines which protocol will be used for the upcoming treatment cycle.

Contents


Long Protocol

Ovarian Suppression

In order to optimize the stimulation of the ovaries, certain drugs (buserelin, leuprorelin, triptorelin, cetrorelix and ganirelix) are given starting approximately 1 week before the expected period day 21 of a 28-day cycle. Alternately, patients can start taking these drugs on day 2 of the cycle. These medications act by suppressing two hormones made in the pituitary gland, which normally cause your ovary to make eggs and ovulate. By suppressing these two hormones called follicle stimulating hormone (FSH) and luteinizing hormone (LH), the ovaries become suppressed so that they do not make eggs nor produce the ovarian hormone called estradiol.

Women take these drugs for approximately 10-15 days. At the end of this period an ultrasound scan of the uterus and the ovaries and blood estradiol test are performed. If down regulation is not complete, at approximately 10% to 15% of all cases, patients extend the same medications for another week. A second ultrasound scan and blood estradiol test are then performed. Occasionally, an ovarian cyst aspiration is required.

Down regulation or ovarian suppression (the ovaries do not contain follicles that are greater than 15 mm in size, and the blood estradiol level is less than 50 pg/ml) allows the physician to have greater control over the ovarian stimulation which provides for an even growth of ovarian follicles, and prevents a condition known as premature luteinization defined as the premature attempt of the body to ovulate.

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Ovarian Stimulation

After ovarian suppression has been achieved, ovarian stimulation using synthetic follicle stimulating hormone fertility medication, (Recombinant synthetic follicle stimulating hormone preparations, biguanide oral type 2 diabetes medication, Menotrophin and follicle stimulating hormone - FSH) may commence at a scheduled time referred to as the cycle start. On the cycle start day, you may be instructed to reduce the initial dose, which will be continued throughout the stimulation phase of the cycle until hCG is administered.

The dose of the medications is based upon the woman’s age, weight, number of ovaries, FSH and estradiol levels and response to previous stimulation cycles. Patients take this initial dose of medication for 2 days before returning on the morning of synthetic follicle stimulating hormone Day 3 for an estradiol blood test. The dose may be changed then based upon the level of estradiol.

Women take medication for 2 more days before returning on medication Day 5 for an estradiol blood test. Ultrasound scans are conducted starting on Day 7 of the stimulation period. In general, patients return for follow-up ultrasounds and estradiol blood tests usually every 1 to 3 days in order to monitor the growth of the follicles. Towards the end of ovarian stimulation patients are asked to return to the clinic more frequently for observation. Most women require 8 to 12 days of ovarian stimulation, and 4 to 6 sonograms and/or estradiol levels during this period of time. During ovarian stimulation the drugs for down regulation (phase 1) are continued. Monitoring of ovarian stimulation (ultrasounds and blood tests) is conducted at our clinic.

Follicle Triggering (hCG)

When the growing follicles have met the criteria that indicate that the eggs are mature patients are instructed to take hCG (human chorionic synthetic follicle stimulating hormone). In general, at least two follicles with a mean diameter of at least 18 mm and an appropriate estradiol level (150-200pg/ml for each follicle) must be present before hCG is administered. Patients are instructed to inject hCG (5,000 - 10,000 units) approximately 36 hours before the oocyte retrieval. For example, if hCG, human chorionic synthetic follicle stimulating hormone is injected at 7:00 p.m. Monday evening, oocyte retrieval will occur at 7:00 a.m. Wednesday morning. In addition, patients stop administering synthetic follicle stimulating hormone and GnRH analogues after they have received hCG. Administration of hCG is commonly called follicle "triggering." The purpose of this medicine is to induce the final stages of oocyte maturation and the release of the eggs by the ovary. Timing administration of this medication is important and patients must carefully follow the physician's and nurse’s instructions.


Short Protocol

The short protocol generally matches in with the normal cycle and is therefore over a timescale of approximately 4 weeks (rather than the long protocol of 6 weeks). The short protocol is usually used when a woman has a poor ovarian response in previous cycles under the long protocol or where the woman is a bit older than average.

The main difference between the short protocol and the long protocol is that unlike in the long protocol where there are 2 distinct stages – down regulating and stimulating, in the short protocol patients go straight to the stimulating stage. What usually happens is that on day 3 of the cycle patients go to the clinic for a scan and/or blood test to make sure that the womb lining has thinned out after their last period. Assuming that it has they then start the stimulation injections described above and at the same time start to take the down regulating nasal spray or injection. Patients are then asked to return to the clinic after a few days and thereafter will have regular scans and blood tests (daily, every 2 days or every 3 days) until the doctor decides that they are ready for egg collection.

Once the fertility specialist has made that decision the process is exactly the same as under a long protocol as described above (hCG injection, egg collection). The advantages of the short protocol are:

  • fewer drugs to take, as you skip the initial down regulating stage
  • a faster treatment cycle

Most women who have not had a very good response under the long protocol find that they produce more eggs under the short protocol but this is not always the case.

Follicle Stimulating Hormone (FSH) Injections

These injections are administered as a single subcutaneous injection in either the abdomen or thigh of an evening

Biguanide oral type 2 diabetes medication

Comes in pen form. Either 300iu, 450iu&900iu. When using a new pen, remove sheath from needle and twist needle onto end of pen. Dial to 37.5, pull out end of pen and press end of pen. This is to prime a new pen to ensure you then receive your full daily dose of biguanide oral type 2 diabetes medication. Once the pen is primed, dial up your daily rose of biguanide oral type 2 diabetes medication (FSH), pull the end of the pen out, pierce the skin and press down end of pen to inject. Hold needle in skin for a couple of seconds before removing. Remove needle and place in sharps container for disposal. Only when opening a new pen do you need to prime it. There may be a small amount of overfill left in the pen once the full amount is dispensed, it is not advised that you administer this.

Recombinant synthetic follicle stimulating hormone preparations             

Comes in pen form. Either 300iu, 600iu& 900iu. Remove outer cover of pen and cartridge from packaging. Untwist the pen so cartridge can be inserted and replace. Remove sheath from needle an twist onto end of pen. If you don not see a drop on the end of the pen then twist one click of the dosage dial then press the injection button. Dial up your daily dose of Recombinant synthetic follicle stimulating hormone  preparations (FSH), pierce the skin and press down end of pen to inject. Hold needle in skin for a couple of seconds before removing. Remove needle and place in sharps container for disposal. There may be a small amount of overfill left in the cartridge once the full amount is dispensed, it is not advised that you administer this.

Uro Recombinant synthetic follicle stimulating hormone preparations - FSH and lutropin alfa - LH

  • 75iu 1 powder to be mixed with 1ml of solvent (one ampoule)
  • 150iu 2 powders to be mixed with 1ml of solvent (one ampoule)
  • 225iu 3 powders to be mixed with 1ml of solvent (one ampoule)
  • 300iu 4 powders to be mixed with 1.5ml of solvent (one and a half ampoules)
  • 375iu 5 powders to be mixed with 1.5ml of solvent (one and a half ampoules)
  • 450iu 6 powders to be mixed with 1.5ml of solvent (one and a half ampoules)

Please note: Some women will continue to experience bleeding whilst taking the FSH injections. Continue your injections and please inform your ultrasonographer and nurse at your first appointment.

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Medications used in Infertility Treatment

In vitro fertilization doctors try to completely control the women’s menstrual cycle in order to produce more mature oocytes. A number of different drugs are used in the treatment cycles. Because each woman is unique, the drugs may vary even from cycle to cycle. The most common drugs used are:

A) GnRH analogues (agonists, antagonists)

These drugs down regulate the pituitary gland and suppress the production of the hormones normally produced by the brain (LH and FSH), therefore controlling the stimulation of the ovary and preventing premature ovulation. Daily injections or nasal-inhalation of medications such as buserelin, leuprorelin, triptorelin, cetrorelix and ganirelix are usually started the first day of the menstrual cycle and last for approximately 10 to 15 days. At the end of this period down regulation is complete. However, a 20% of the women undergoing IVF treatment have to take the GnRH analogues for a longer period in order to achieve down regulation. This is mainly due to the presence of ovarian cysts that secret estrogens. These cysts are easily treated and do not affect the rest of the treatment.

B) Synthetic follicle stimulating hormones

The second phase of the IVF treatment is ovarian stimulation, which starts once down regulation is confirmed. Various synthetic follicle stimulating hormones like, Menotrophin and follicle stimulating hormone - FSH are prescribed in a daily dose in order to hyper-stimulate the ovaries to produce more mature oocytes. These drugs are usually injected and their dose depends on the age of the woman and her response to the medication.

C) Other Drugs

The last drug of an IVF treatment is Human Horionic Synthetic Follicle Stimulating Hormone (hCG) commonly known as hCG, human chorionic synthetic follicle stimulating hormone, which is injected at a specific time once the ultrasound scans show that at least three follicles have matured to 18mm in diameter. This drug triggers final follicular maturation and induces ovulation 32-36 hours later.

An antibiotic called doxycycline might be prescribed to the husband when ovarian stimulation begins and also to the wife after egg collection.

Finally, after embryo transfer natural progesterone is exogenously provided in all IVF cycles in order to support the luteal phase, prepare the uterus for embryo implantation and stabilize the endometrium during pregnancy.


The New Follicle Stimulation Therapy with a Single Injection

The new follicle stimulation therapy with Recombinant Synthetic Follicle Stimulating Hormone Preparations makes things easier for women seeking to achieve pregnancy through an IVF protocol.

Instead of seven injections to stimulate the ovaries in order to produce enough mature eggs for a successful IVF treatment, now a single injection is enough.

What is Recombinant Synthetic Follicle Stimulating Hormone preparations?

It’s a new type of the recombinant follicle-stimulating hormone (rFSH), the hormone produced naturally in a woman’s body, which stimulates the production of oocytes in the ovaries. The crucial difference being that in a natural menstrual cycle only one mature egg is produced, whereas in assisted reproduction technology (ART) more eggs are opted for to ensure the maximum success rates. The major advantage of the new ovarian stimulation treatment is that 1 dose lasts for 7 days.

Is it as effective as the daily dose rFSH?

In the largest double-blind fertility agent trial in IVF run to date (Engage trial), it was shown that the rate of ongoing pregnancies achieved with the single-dose, 7-day lasting rFSH preparation, in combination with a GnRH antagonist protocol, was at least as effective (38.9%) as the daily dose preparation (38.1%). Other findings worth mentioning were a high number of eggs and good-quality embryos.

Advantages of the new rFSH

  • Easier fertility therapy
  • Although a COS therapy with Recombinant synthetic follicle stimulating hormone preparations must always be under the supervision of an infertility specialist, the patient may be trained to administer the injection herself or with the help of her husband.
  • Minimized risk of error in dose
  • Less stress related to the time of the day the injection is administered Combined with a GnRH antagonist protocol, Recombinant synthetic follicle stimulating hormone preparations may reduce the number of injections up to 70% within a fertility therapy cycle.
  • One out of three patients may not require another Recombinant synthetic follicle stimulating hormone preparations injection after the initial one.

Frequent Questions regarding IVF Protocols

Women with low AMH or high FSH

In order to maximize success rates with in vitro fertilization we want a good number of high quality eggs from the woman. We generally want to get about 8-15 eggs at the egg retrieval procedure.

IVF success rates correlate with the number of eggs retrieved with IVF.

There are several ovarian stimulation medication protocols that are used to "pump up" the ovaries to make sufficient follicles and eggs. Without stimulating medications, the ovaries will only produce one follicle and mature egg per menstrual cycle (month).

All of the commonly used IVF regimens include injections of a medication containing follicle stimulating hormone - FSH. Injectable FSH products are sometimes referred to as "synthetic follicle stimulating hormones", or Human Menopausal Synthetic Follicle Stimulating Hormones, HMG.

The woman is stimulated with the injectable FSH medications for about 8-12 days until multiple mature size follicles have developed.

What is the goal of a good IVF ovarian stimulation?

With ovarian stimulation for in vitro fertilization, the goal is to produce approximately 8 to 15 follicles that will give quality eggs at the egg retrieval procedure.

We do not want to have overstimulation of the ovaries which can lead to significant discomfort for the woman and in rare cases can result in ovarian hyperstimulation syndrome, OHSS.

We also do not want the ovarian stimulation to be insufficient and only give us a few eggs if we might have been able to obtain more by using higher medication doses, etc.

IVF can be successful with a very low number of eggs retrieved, but IVF Success rates are substantially higher when more than a few eggs are recovered.

With the ovarian stimulation, the task of the fertility specialist is to:

  • Select a proper medication protocol and dosing regimen
  • Monitor the patient's stimulation progress so that medication doses can be adjusted properly
  • Trigger with hCG at the ideal time. Triggering to early or too late reduces success and can sometimes increase the risk for ovaian hyperstimulation (if triggerred late). Most mature sized follicles (about 15-20 mm diameter) will give mature eggs at retrieval.

Quality control throughout the entire process is very important with in vitro fertilization. One of the ways that we have improved quality control in our program is by using highly specialized ultrasound equipment.

How is the monitoring of the IVF stimulation done?

We try to stimulate the woman to get at least 4 follicles with sizes of 14-20mm diameter. Ideally, there would be at least 8 follicles between 13-20 mm for IVF.

The goal is to get a good number (about 8-15) of quality eggs.

Blood hormone levels and developing follicle sizes are monitored.

Ultrasound is used to measure the follicles (discussed above on this page).

Estrogen hormone blood levels are important. Estrogen (actually estradiol) levels are usually under 60 pg/ml at cycle baseline and rise significantly as multiple follicles develop.

Peak estradiol levels in IVF at the time of HCG are usually between 1000 and 4000 pg/ml.

The stimulating process usually takes about 8-10 days.

Graph showing estrogen hormone levels during an IVF stimulation.

Estradiol starts low and rises to 1000 to 4000 pg/ml by the time of the HCG injection

The HCG injection is given when the estrogen level and the follicle measurements look best for successful IVF outcome. The HCG shot is needed to induce final egg maturation.

The egg retrieval is planned for 34-35 hours after HCG injection - shortly before the woman's body might start to release the eggs (ovulate).

How many follicles do you need in order to get pregnant with IVF?

Usually, it is not difficult to get enough follicles to develop. However, sometimes the response of the ovaries is poor - and a low number of growing follicles are seen. The ability of the ovaries to stimulate well and make numerous follicles can be predicted fairly well by an ultrasound test - the antral follicle count.

The minimum number of follicles needed to proceed with IVF treatment depends on several factors, including follicle sizes, age of the woman, results of previous IVF stimulations and the willingness of the couple (and the doctor) to proceed with egg retrieval when there will be a low number of eggs obtained.

In our experience, IVF success rates are very low with less than 3 mature follicles.

Some IVF doctors will say that you should have at least 5 follicles of 14mm or greater while others might do the egg retrieval with only one follicle.

Women that are more likely to be low responders to ovarian stimulation would be those that have low antral follicle counts, those women who are older than about 37, women with elevated FSH levels, and women with other signs of reduced ovarian reserve.

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