• Why we use drugs
• Why drugs are necessary
• Do the IVF drugs reduce my ovarian reserve?
• Possible side effects of IVF drugs
• Which drugs are used?

Why we use drugs

Fertility drugs (Eugonia archive)

It has been shown that pregnancy success rates following IVF increase when more than one good quality embryos are transferred to the uterus. However, embryos formed after IVF do always have the desirable quality. Therefore, in order to have the ability of selection, we need several embryos, which will derive from the fertilisation of several eggs. The eggs, in turn, will be retrieved from several follicles. We therefore use drug protocols of controlled ovarian stimulation to promote the development of multiple follicles.

Why drugs are necessary

The drugs used are analogues of natural hormones in order to create a pharmaceutically controlled reproductive cycle. They aim at the following:

• The recruitment and maturation of multiple follicles
• To prevent untimely ovulation and loss of eggs due to early rise of LH. The drugs temporarily disrupt the communication between the pituitary and the ovaries leadin to downregulation of the glands (using GnRH agonists or antagonists)
• The selection of the ideal time of ovulation (with the application of hCG)
• To modulate the uterine environment for the support of the embryo (use of progesterone)

Do the IVF drugs reduce my ovarian reserve?

No, as the drugs rescue and promote the maturation of follicles that would otherwise degenerate through atresia. Atresia is the degeneration of follicles initially recruited in a single menstrual cycle.It is worthwhile noting that the ovary contains approximately 300-400.000 follicles, of which only 400 mature during a woman's reproductive life (the rest degenerate via atresia, i.e they become atretic).

Possible side effects of IVF drugs

Mild symptoms from certain drugs and rare allergic reactions (hot flushes, headaches, sweating, blocked nose) are practically insignificant and can be easily overcome.Ovarian hyperstimulation syndrome (OHSS) is a side effect of controlled ovarian stimulation. It occurs in a small percentage of women beginning treatment. In the majority of cases it can be prevented and when it occurs it can be treated.The danger of subsequent ovarian, uterine or breast cancer is similar with the general population as demonstrated by large epidemiological studies.Also see: Ovarian Hyperstimulation syndrome

Which drugs are used?

The main drugs used are:

GnRH analogues

Pharmaceutical analogues of the hormone GnRH intend to inhibit the premature rise of LH that causes ovulation. In this way we are able to prevent the undesirable rupture of follicles before the egg collection. In the past, before the use of GnRH analoguesabout 20-33% of cycles were cancelled due to premature ovulation.GnRH analogues are classified in two categories:

• GnRH agonists (trade names: Arvecap, Daronda, Suprefact, Gonapeptyl) and
• GnRH antagonists (trade names: Orgalutran, Cetrotide)

 See: GnRH analogues, GnRH agonists, GnRH antagonists

Gonadotrophins

They are synthetic pituitary gonadotrophins and are applied in order to stimulate the development and maturation of multiple follicles. They are classified in the following categories: 

• Recombined gonadotrophins (recFSH, recLH)Puregon (recombined FSH)Gonal-F (recombined FSH)Pergoveris (mixture of recombinant FSH, recombinant LH)
• Urinary gonadotrophins (hMG)Altermon (purified FSH)Metrodin-HP (purified FSH) andΜerional – Bravelle (hMG with FSH-LH mixture)
• Corifollitropin- α (corifollitropin alpha, with commercial name Elonva)

 See more: Gonadotrophins

Human chorionic gonadotrophin (hCG)

This is the last drug to inject during your treatment. It is applied once at a specific time (36-38 hours before egg collection), when the maturity of the follicles is adequate. Drugs: Ovitrelle (recombined hCG) and Pregnyl, Profasi (urinary hCG)These drugs are available in several forms:

• ready to use injectable solution
• powder that is mixed with a special diluent to produce the final solution
• pre-filled cartridge or pen-like syringe

 Injections are given subcutaneously or intramuscularly, depending on the instructions given. The pen is graduated in international units so you can apply the drug yourselves with precision and safety.See: Human chorionic gonadotrophin (hCG)

Progesterone

It is usually used after the embryo transfer to hormonally support the luteal phase and therefore the environment of the uterus that will receive the embryo. It is available as a vaginal cream (Crinone) or pills (Ultrogestan).Other medicines like estrogens, cortisone, antibiotics and aspirin may be used if deemed necessary. In some cases contraceptive pills are used before the start of the treatment program.See: Progesterone

During the course of IVF treatment, the following drugs may also be used.

Antibiotics

The male partner receives prophylactic administration of antibiotics when the female partner starts her ovulation stimulation and the female partner receives prophylactic administration of antibiotics following egg collection, according to the unit's instructions. Vibramycin is usually the antibiotic used.

Corticosteroids

In special cases, drugs that contain cortisone may be used (Medrol pills or Dexamethasone). In a recently published study of our unit, that had a very good response in the international scientific press, it was shown that the use of corticosteroids is related with the prevention of ovarian hyperstimulation syndrome (Administration of Methylprednizolone to prevent severe ovarian hyperstimulation syndrome in patients undergoing in vitro fertilization.) T. Lainas et al., Fertil. Steril. 2002;78(3):529-533). See the publication

In every case, special care should be taken and the doctor's instructions should be followed to the letter when starting and especially when stopping cortisone administration, which should be done by gradually reducing the dose, according to a specific time-plan.

Oestrogens

In certain cases, for instance when the protocol of preparing the endometrium for embryo transfer without having an egg collection is used, e.g. in the case of a frozen embryo transfer, oestradiol is administered orally (Estopause, Cyclacur; only the white pills in the package contain 17- β oestradiol) or with transdermal patches (Dermestril or Estraderm).

Clomiphene citrate

It is an "older" drug with proven results, that has anti-oestrogen action. This drug is used in certain ovarian stimulation protocols, either on its own, or in combination with gonadotropins. Its anti-oestrogen action "tricks" the pituitary gland into thinking that there is no oestrogen available, which results in an increase in the release of endogenous FSH and development of the follicles.

Clomiphene is available in pills, with the commercial names of Clomiphene citrate, Serpafar and Clomid. If the stimulation is relatively mild, clomiphene is mainly used in ovulation induction or in intra-uterine insemination cycles and also in some other rare assisted reproduction treatments.

It is usually used after embryo transfer to hormonally support the luteal phase of the menstrual cycle. According to the literature, the luteal phase of the menstrual cycle needs progesterone support, especially in treatment cycles that a GnRH analogue has been used.

This hormone is available in the form of a vaginal gel (Crinone), or in pills (Utrogestan). These pills may be administered orally, vaginally (as suppositories), or both orally and vaginally. The local absorption of progesterone from the vagina is very good and has proven to have excellent results.

This is the last injectable drug of the treatment. It is administered in a single dose at a specific time (around 36-38 hours prior to egg collection) when the follicular development is deemed satisfactory to proceed with the egg collection.

hCG is a hormone that is normally secreted during the placenta development. Its measurement is used for the detection of pregnancy. However, an area of the hCG molecule is very similar to the LH molecule and it is therefore possible for the hCG to bind to the LH receptors and mimic its action. This means that the administration of hCG in a single powerful dose can "trick" the ovary and induces follicle rapture around within the next 36 hours (please note that the normal hormonal signal of ovulation in the human body is LH, which is released in a large surge when oestradiol levels go over a certain point).

hCG is available in a pharmaceutical form for intramuscular injection with the commercial names Pregnyl or Profasi (urinary hCG). During the last few years there is also a recombinant form of hCG (r-hCG), with the commercial name Ovitrelle. Ovitrelle is available in a pharmaceutical form for subcutaneous injection due to its high purity.

Corifollitropin-α is a new recombinant gonadotropin (FSH) that has been designed for ovarian stimulation. It is administered in a single injection in the beginning of the ovarian stimulation and can initiate and sustain multiple follicular development for up to 7 days. Also see: The new drug Corifollitropin-a

It is well know that pituitary hormones FSH and LH are called gonadotropins because they act on the gonads (testicles-ovaries) and promote their function. Nowadays, synthetic and pharmaceutically produced pituitary gonadotropins are available which are administered for the development and maturation of multiple follicles. The drugs that are available are the recombinant and the urinary gonadotropins.

These hormones are administered by injection and they are commercially available:

• in a pre-mixed ready to used solution,
• in a powder that needs to be mixed with a special diluent in order to produce the injectable solutio
• pre-filled cartridge or pen-like syringe.

The pen-like syringe is marked in units so as the woman can administer subcutaneously the solution by herself with precision and safety.

Recombinant gonadotropins

They are new reproductive era drugs. Molecular biology has allowed pharmaceutical companies to apply the developments in recombinant DNA technology in drug production. Two forms of the human FSH gene have been isolated and they have been inserted and integrated in genetically modified cells. These cells can be cultured industrially and can therefore produce and release large quantities of natural human FSH, which can then easily be isolated in an almost pure chemical form.

Nowadays, these gonadotropins are available commercially under the generic name "recombinant FSH". Their commercial names are Puregon and Gonal-F. The chemical purity of these products allows their subcutaneous administration but the can also be administered intramuscularly. The way they are administered does not affect their biological action. The other gonadotropin called LH is also available as a product of the same technology with the commercial name Luveris.

Urinary gonadotropins

They are "older" technology drugs. For many decades, gonadotropins that were used in assisted reproduction came from the urine of postmenopausal women. There was a complicated and expensive system in place for the collection of the urine (usually from women monasteries) and the isolation of hormones, a true struggle of the pharmaceutical industry of which little was known to the general public. With the sudden increase in gonadotropin demand due to the wider application of assisted reproduction, this system quickly reached its definite capacity, in the beginning of the 90's.

The drugs of that era contained a mixture of the two gonadotropins (FSH and LH) in various doses, with the generic name hMG (human menopausal gonadotropin) and were commercially available with the names Pergonal, Humegon, Pergogreen, Humegon FD. Their administration had to be done intramuscularly, due to their rather small grade of chemical purity. During the middle of the 90's, technology evolved and new drugs that contained purified FSH (Metrodin-HP) which were possible to be administered subcutaneously become commercially available. Nowadays, there are still urinary gonadotropins available for intramuscular or subcutaneous injection with the commercial names Altermon, Metrodin-HP and Menogon. Altermon is highly purified product and Menopur, Merional and Bravelle contain a mixture of FSH/LH in a 1:1 ratio.

The primary mechanism of action of GnRH antagonist analogues of is to compete with the natural GnRH hormone. GnRH antagonists bind to the GnRH receptor which causes a suppression from the very beginning of their administration, due to the occupation (and not a reduction in the numbers) of GnRH receptors. They thus result in the reduction of FSH and LH gonadotropin production. The suppression of the pituitary gland function is achieved in minimum time (almost straight after) following their administration.

The pharmaceutical production of GnRH antagonist analogues occurred after that of GnRH agonist analogues. After setting up the daily GnRH antagonist dosage, five multicenter phase III studies followed (2000-2001) in Europe, Middle East and USA, in order to extract conclusions for their effectiveness in clinical practice, the comparison of their results with GnRH agonists, etc. Since then, numerous original studies and meta-analyses have been published with regard to the experience of administering GnRH antagonists on a preselected day (typically, the 6th day of stimulation) and the so called flexible administration protocol.

When are they used

Antagonists are administered during the treatment with gonadotropins, in the current menstrual cycle. The main innovation of antagonists is that their administration, even for a few days prior to follicular rupture, causes an immediate suppression of pituitary function that results in the prevention of the LH surge.

Commercial names

GnRH antagonists are available with the following commercial names: Orgalutran (Ganirelix) and Cetrotide (Cetrorelix), in a pre-mixed dilution ready to be used by subcutaneous injection.

The action of GnRH agonist analogues is similar to that of the natural hormone.

The GnRH agonist analogues, at the start of their administration and also in the case of their intermittent use, result in the stimulation and rise in the release of FSH and LH gonadotropins, through a flare-up mechanism. This happens because they stimulate the synthesis of GnRH receptors in the gonadotropic cells of the hypophysis (pituitary gland).

If the administration of GnRH agonists is prolonged, the ovarian function is suppressed due to the reduction of gonadotropin release. This reduction occurs due to the extended occupation of the GnRH receptors by the GnRH analogues and also due to the reduction of the number of GnRH receptors in the gonadotropic cells of the hypophysis. This phenomenon is also known as down-regulation or pituitary desensitization and has been considered a "paradox" in its first publication in 1975. Nowadays, we are taking advantage of this "paradox" to achieve suppression of the pituitary function by GnRH agonist analogues administration.

When are they used

GnRH agonists are administered towards the end of the last menstrual cycle (in the middle of the luteal phase, meaning around 7 days before the menstrual cycle is due) or in the beginning of the menstrual cycle and they progressively result in the suppression of the pituitary function. Since the pituitary gland is no longer active, the normal course of the menstrual cycle is suspended, the follicles do not mature and they do not rapture, and this allows us to administer gonadotropins in such doses to stimulate multiple follicle development in the time that we chose. Nonetheless, the continuous administration of GnRH analogues is obligatory, during the entire stimulation phase.

Commercial names

GnRH agonists that are available in Greece have the following commercial names: Arvekap (Triptorelin), Daronda (Leuprolide), Suprefact (Buselrelin) and Gonapeptyl. These come either in a pre-mixed dilution ready for subcutaneous injection, or in the form of a powder that needs to be mixed with a special diluent in order to become an injectable solution, or in a nasal spray. Their active ingredients are all similar. GnRH agonists administration may result in a little uterine bleeding (pseudo-period). Possible side-effects of treatment with GnRH agonists are a stuffy nose, hot flashes, headaches, night sweats, etc.

They are pharmaceutical analogues of GnRH hormone which suppress the premature surge of Luteinising Hormone (LH) that triggers ovulation. In this way, premature ovulation prior to oocyte retrieval is prevented. Prior to the use of GnRH analogues, there was a 20-30% cancellation rate of treatment cycles due to premature ovulation.

GnRH hormone is produced in the hypothalamus area and results in the production, storage and release of gonadotropin hormones FSH and LH from the pituitary gland. GnRH is released periodically (in waves) every one to three hours, depending on the phase of the cycle and is then followed by the release of the gonadotropins from the pituitary gland.

Why do we use GnRH analogues

It is well established that the rise and surge in LH results in the final oocyte maturation and ovulation. In IVF treatment we prefer to schedule ovulation at a specific time. A premature surge in LH would result in follicle rupture prior to egg collection and loss of the ovulated oocytes. The control of LH surge by its suppression is of great importance and has significantly reduced cycle cancellation. This control is achieved through the use of GnRH analogues.

Morula.

The morula is observed on day 4 and is formed after the compaction and fusion of blastomeres of the dividing embryos. As the morula continues to develop, fluid starts to accumulate forming a cavity, the blastocoel, giving rise to the blastocyst.

Blastocyst

Expanded blastocyst.

The blastocyst forms after 5 days of embryo culture. The mature blastocyst is characterized by expansion of the blastocoel due to accumulation of fluid, the thinning of the zona pelucida,and the formation of two distinct cell layers, the inner cell mass, that will form the embryo, and the trophectoderm, that will form the placenta.

The blastocyst for the evaluation of embryo viability

Development to the blastocyst stage is a sign of normal development and high developmental competence. It has been shown that embryos reaching the hatching blastocyst stage have double chances for implantation. At Eugonia, blastocyst formation rate is 54%. This high percentage reflects optimal laboratory conditions and experience of the scientific staff.

Activation of the embryonic genome occurs between 4 and 8 cells. Therefore, the contribution of the paternal DNA and the assessment of an embryo as a whole can be better performed 5-6 days after oocyte retrieval. This is particularly important for cases with poor sperm quality (oligoasthenozoospermia) or testicular biopsy.

Continuous development of culture media and laboratory conditions allow the development of embryos in vitro for up to 6 days without compromising their viability. However, there is a theoretical chance that the uterus may provide a more favorable environment for embryo development. Practically, however, in an IVF laboratory with high experience and quality control, embryos of higher developmental competence will grow to the blastocyst stage, providing the Embryologist a strong criterion for embryo selection. For this reason, pregnancy rates after transfer of blastocysts is higher and reaches 72% for women of all ages at Eugonia.