Ovulation stimulation drugs and protocols in II level assisted fertilization

When a couple undergoes IVF treatment, whether it is IVF or ICSI, it is important to be able to obtain as many oocytes as possible. Here because.

The extracted oocytes will be used to try to obtain as many embryos as possible .

For this reason, the woman undergoes controlled ovarian stimulation and then ovulation induction when the follicles have reached the desired size (about 17-18 mm). Approximately 34 hours after the induction of ovulation, the woman will undergo an oocyte retrieval (the “pick-up”) in the hospital.

In a natural menstrual cycle we know that usually only one follicle matures and bursts to release the oocyte at the time of ovulation.

The aim of stimulation, on the other hand, is to obtain the simultaneous maturation of several follicles in order to have the greatest number of oocytes possible, without however falling into the risk of hyperstimulation.

The stimulation protocols are customized according to the woman’s ovarian reserve.

A woman’s ovarian reserve is what is left of her follicle stock. At birth, a woman has 1-2 million follicles which decrease to 300,000-400,000 at the first menstruation (menarche). Less than 1000 remain in menopause , but these are follicles that are no longer able to respond to stimulation.

The different ovarian stimulation protocols

There are different types of stimulation protocols that require the use of three main categories of drugs:

• drugs that stimulate multiple maturation of follicles
• drugs that inhibit ovulation
• drugs that induce ovulation

Depending on the type of drug and the timing of administration, you can have

• long stimulation protocols
• ultra-long stimulation protocols
• short stimulation protocols
• ultra-short stimulation protocols
• Double stimulation protocols (duostim) 

When a couple begins an assisted fertilization process, they are overwhelmed by a lot of information, and by a long series of names of drugs and times that are part of the personalized treatment plan .

At first listening it may seem complicated but once you start you will see that these are essentially injections to be given at certain times of the day, paying particular attention to the concentrations that are defined when the treatment plan is delivered.

Concentrations may be changed by your doctor during stimulation based on how your body responds to the drugs.

In fact, during the stimulation the woman is frequently subjected to ultrasound monitoring and blood sampling, to monitor how she responds to the stimulation and verify how the circulating hormone levels vary.

Drugs that stimulate the growth of as many follicles as possible

The drugs that induce the growth of the follicles, i.e. with a follicle-stimulating action, are the gonadotropins (menopausal or recombinant). These are molecules that act on the ovaries in women, determining the development and maturation of the ovarian follicles.

Examples of gonadotropins and drug names commonly used in treatments:

• Menopausal FSH (drug name  Fostimon )
• FSH Recombinants:
  • Follitropin alfa (drug name Gonal-F )
  • Follitropin beta (drug name Puregon )
  • Follitropin delta (drug name Rekovelle )
  • Corifollitropin alfa: (drug name Elonva )
• Recombinant LH: Lutropin alfa (drug name Luveris )

There are combinations of FSH and LH also in this case human or recombinant:

• Menotropin: highly purified preparation of FSH and LH in a 1:1 ratio extracted from the urine of menopausal women (drug name Meropur )
• Follitropin alfa + Lutropin alfa (drug name Pergoveris )

There are also gonadotropins biosimilar to follitropin alfa on the market and they are two specific drugs that generally have lower costs than the others: Bemfola and Ovaleap.

The choice of the type of gonadotropin and therefore of drug depends on the patient’s fertility problem and it will be the doctor who follows the woman who will evaluate the most suitable pharmacological protocol.

Drugs that block ovulation

When gonadotropins are administered to obtain the growth of many follicles, there is a risk of an early LH surge  which determines the patient’s ovulation. This is not good because the purpose of the stimulation is also to pilot ovulation so as to be able to pick up the oocytes in the operating room at the right time, ie when there is the greatest possible number of mature oocytes.

For this reason, drugs are used to prevent the spontaneous peak of the LH hormone.

These drugs are divided into two categories due to the different mode of action:

• GnRH agonists (common drug name: Decapeptyl, Gonapeptyl, Enantone )
• GnRH antagonists (commonly used drug name: Cetrotide, Orgalutran )

Recall that GnRH ( Gonadotropin Releasing Hormone) is a hormone produced by the hypothalamus and acts on the pituitary by regulating the production of FSH and LH.

Drugs that induce ovulation

These are human cornic gonadotropins (hCG, commonly used drug name Gonase ) produced by the placenta during pregnancy. These gonadotropins are very similar in structure to the hormone LH. They are administered by intramuscular or subcutaneous injection when at least 2-3 follicles exceed 17-18 mm. Ovulation occurs on average 36 hours after injection.

In the assisted fertilization pathways, the oocyte retrieval must take place approximately 34 hours after the injection. For this reason, doctors indicate the precise time in which the woman will have to have the Gonasi puncture.

Ovulation stimulation protocols in II level assisted fertilization treatments

The definition of the ovulation stimulation protocols in second level assisted fertilization treatments, i.e. those adopted to obtain the maturation of as many follicles as possible, is carried out by the PMA clinic doctor, based on the patient’s ovarian reserve and her fertility or general health.

The goal is not only to recover as many oocytes as possible but also to avoid the risk of hyperstimulation.

What is the FSH dose that is given to women during ovulation stimulation?

There is no set amount. It depends on some factors which are represented by:

1. baseline FSH levels of the individual patient
2. age of the patient
3. patient’s body mass index
4. antral follicle count
5. genetic polymorphisms

On average, the amount of FSH administered is between 150 and 225 IU per day, but this dose can also be adjusted during stimulation based on how the patient responds.

Protocols with GnRH analogues

The stimulation protocols are divided according to the type of drug used and the length of the treatment that follows.

They are distinguished in:

• protocols with GnRh agonist ( Decapeptyl, Gonapeptyl, Enanthone) : short, ultrashort, long and ultra long,
• protocols with GnRH antagonist ( Cetrotide, Orgalutran)

Long protocols involve administering the GnRh agonist in the luteal phase of the previous cycle. When estrogens are lower than 50 pg/ml (on average 15 days after the start of treatment), gonadotropins are started up to the induction of ovulation when at least 2-3 follicles have a diameter of 17-18 mm . They are the most used protocols.

The ultra-long protocols : we start with the administration of the GnRH agonist in the two cycles preceding the one in which the oocyte retrieval will take place. It is used in patients suffering from endometriosis or adenomyosis.

The ultra-short protocols provide for the administration of GnRh analogues from the second-third day of the menstrual cycle in conjunction with the gonadotropins. It is mainly used in women who respond poorly to stimulation ( poor responders ) or who have a low ovarian reserve.

In short protocols the agonist is started by day 3 of the menstrual cycle and gonadotropins are administered 2 days after starting the agonist. It is used in women who have a good ovarian reserve. Also in this case the induction of ovulation is done with gonases when at least 2-3 follicles have a diameter of 17-18 mm.

GnRH antagonist protocols can be fixed or flexible. They provide for the administration of gonadotropins from the 2nd-3rd day of the menstrual cycle. In the fixed protocols, the antagonist is administered from the 5th day, while in the flexible protocols, the antagonist is administered only in the presence of a follicle larger than 14 mm, or estradiol values ​​greater than 200 pg/ml, or endometrium thicker than 6.5 mm. Ovulation induction can be done either with gonase or with GnRH agonists. They are used in patients with PCOS (micropolycystic ovary) because there is less risk of overstimulation than other protocols.