In order to get more of the follicles (and oocytes) which are recruited during a particular menstrual cycle, fertility specialists use medical schemes (protocols) to ensure controlled ovarian stimulation.
Currently, fertility drugs contain the same hormones that the body normally uses during a woman’s reproductive cycle. Oocyte and embryo quality depend greatly on choosing the appropriate stimulation protocol.
Why are fertility drugs important?
Fertility drugs are synthetic analogs of natural hormones that create a medically controlled reproductive cycle. Fertility drugs are used to:
⇒ Recruit and grow multiple follicles (gonadotropin analogs)
⇒ Prevent premature ovulation and oocyte loss due to premature LH rise.
⇒ To correctly time the induction of oocyte final maturation and release (β-chorionic gonadotropin analogs).
⇒ To support the uterine environment until it becomes receptive to implantation of an embryo (progesterone analogs).
Side effects of IVF drugs
Mild reactions to fertility drugs and rare allergic reactions (hot flushes, headaches, swelling, blocked nose) result in some discomfort but usually resolve quickly without complications.
Ovarian Hypestimulation Syndrome (OHSS) is a medical condition occurring due to medically controlled ovarian stimulation. It is a rare complication that can be usually treated with outpatient care and medication.
Common IVF drugs
It is generally acknowledged that medically controlled ovarian stimulation and ovulation have increased pregnancy success rates in IVF worldwide. Below, you can read about the most common medications recommended by clinicians:
3. β-chorionic gonadotropin
GnRH analogs (GnRHa)
These drugs are divided into GnRH agonists (Brand names: e.g. Arvekap, Daronda, Suprefact, Gonapeptyl, etc) and GnRH antagonists (Brand names: Orgalutran (Ganirelix) and Cetrotide (Cetrorelix).
GnRH analogs are synthetic peptide drugs modeled after the human GnRH and are used to prevent a premature LH surge that would trigger ovulation. Their use prevents premature follicle rupture, before egg retrieval. Prior to the introduction of GnRH analogs in IVF, the average rate of cycle cancellation due to premature ovulation was 20-30%.
As mentioned previously, GnRH is synthesized and released from the hypothalamus. GnRH stimulates the synthesis, storage and secretion of the gonadotropins, FSH and LH, from the pituitary. GnRH secretion is pulsatile, with pulses occurring every one to three hours, according to the phase of the menstrual cycle. Every pulse is followed by secretion of the gonadotropins from the pituitary.
It is known that LH increases and LH surge forces final oocyte maturation and ovulation. In IVF ovulation induction is programmed to occur at a specified time. Premature LH rise would induce follicle rupture, prior to egg retrieval, and subsequent oocyte loss. Controlling the secretion of LH by down-regulation significantly decreased the IVF cycle cancellation rate. Down-regulation is achieved by administrating GnRH analogs.
Nowadays, various synthetic GnRH analogs are available for clinical application. GnRH analogs are high-technology pharmaceutical products that according to their action are classified as agonists and antagonists of GnRH. Their mechanism of action is described below: GnRH analogs are designed similarly to the chemical structure of the natural occurring hormone and attach to GnRH receptors in the pituitary rapidly and with high affinity.
GnRH agonists (GnRHa)
GnRH agonists have similar action to the natural occurring hormone.
GnRH agonists’ continuous or pulsatile administration initially causes FSH and LH (gonadotropins) hyper secretion, known as «flare-up effect». Agonistic molecules activate GnRH receptor synthesis in the gonadotropes of the pituitary.
If GnRH agonist administration is continued, ovarian function is suppressed, due to decreased gonadotropin secretion. LH and FSH suppression occurs due to prolonged agonist receptor occupancy and GnRH receptor internalization in the gonadotropes of the pituitary. This phenomenon is called down-regulation or pituitary desensitization and has been characterized as «paradox». Nowadays, we take advantage of this paradox. Administration of agonistic GnRH analogs down-regulates pituitary function and promotes gonadotropin release suppression.
Agonists are usually administered during the end of the preceding menstrual cycle (mid-luteal phase, around 7 days before the onset of menstruation) or from day 1 of the stimulation cycle and gradually induce pituitary down-regulation. Given that the pituitary is non-functioning, the natural menstrual cycle is disturbed, while follicle maturation and ovulation stops. The administration of gonadotropins in certain doses allows the controlled induction of multiple follicular development. However, agonist administration is continued until the completion of stimulation.
GnRH antagonists (GnRHa)
GnRH antagonists were developed later than agonists. Their action is competitive to the natural occurring hormone. Antagonistic analogs competitively bind to pituitary GnRH receptors and induce hormone suppression immediately, due to GnRH receptor blockade (not due to a decrease in the number of receptors). On this basis, antagonists suppress gonadotropin (FSH and LH) synthesis. Pituitary down-regulation is achieved almost immediately after their administration.
GnRH antagonists are administered during the cycle of controlled ovarian stimulation. The innovation offered by antagonists is that their administration, even when starting a few days before ovulation, immediately suppresses gonadal function, avoiding pre-mature LH surge.
Pituitary hormones FSH and LH are known as gonadotropins since their primary target organs are the gonads (testes – ovaries) and elicit multiple responses. Nowadays, we have synthetic, pharmaceutically manufactured pituitary gonadotropins that are used to induce women to produce a larger number of oocytes. Pharmaceutically manufactured pituitary gonadotropins are divided into two groups: recombinant products and urinary products.
These medications are given by injection and delivery systems include:
> prediluted injectable solution,
> lyophilized powder with a diluent that need to be mixed before injection,
> premixed, prefilled pen or cartridge.
These medications are the latest and most sophisticated so far developed. Molecular biology opened the door to the pharmaceutical industry for the production of recombinant preparations. Genes encoding for the alpha and beta subunits of FSH were isolated and inserted into expression vectors that were transfected into genetically engineered cell lines. These cell lines are cultured in vitro, and produce high quantities of native human FSH, that can be easily isolated as a highly pure product.
Nowadays, these preparations are available and known as «recombinant FSH». Their brand names are Puregon and Gonal-F. Their chemical purity allows subcutaneous administration, even though intramuscular administration is also feasible. The route of administration doesn’t affect their activity. Moreover, recombinant LH is also available under the brand name Luveris.
Urinary gonadotropins are old technology medications. For many decades, gonadotropins used in clinical practice in IVF were derived from postmenopausal urine. There was a complex and expensive network set for the collection of urine (usually from nuns in monasteries) and the extraction of gonadotropins. This was a complex and difficult task undertaken by the pharmaceutical industry, which remains almost unknown to the general public. In the early 90’s, this system almost crashed, as the demand for gonadotropins rose suddenly due to the start of mass application of IVF
These preparations, known as hMG preparations (human menopausal gonadotropin preparations) contained amounts of both gonadotropins (FSH and LH) in various ratios and were commercially available under the brand names Pergonal, Humegon, Pergogreen, Humegon FD. Their administration was intramuscular, due to their impurity. During the mid 1990’s, further purification of hMG led to the release of pure FSH (Metrodin-HP) which could be administered subcutaneously. Today, in addition to the above, menopausal gonadotropins are available for intramuscular or subcutaneous injection, under the brand names Altermon, Metrodin-HP and Menogon. Altermon is a high purity gonadotropin preparation, whereas Menopur, Merional, and Bravelle contain FSH/LH in a 1:1 ratio.
The following are hypopituatary gonadotropins produced through pharmaceutical means:
1. recombinant gonadotropins (rec FSH – rec LH) with brand names Puregon (rec-FSH), Gonal-F (rec-FSH), Pergoveris (a combination of rec FSH – rec LH) and
2. urinary gonadotropins (HMG) with brand names Altermon (purified FSH), Menopur (purified FSH), Μerional – Bravelle (HMG including both FSH-LH)
3. corifollitropin alfa with the brand name Elonva.
Human Chorionic Gonadotropin (hCG)
hCG has been uniformly adopted as the final injectable medication of your treatment. hCG is administered once, 36-38 hours prior to egg retrieval when preovulatory follicles are present.
hCG preparations: Ovitrelle (recombinant human chorionic gonadotropin), Pregnyl, Profasi (urinary human chorionic gonadotropin).
hCG preparations are distributed as:
√ prediluted injectable solution,
√ lyophilized powder with a diluent that needs to be mixed before injection,
√ premixed, prefilled pen or cartridge.
hCG injections are approved for administration by either the subcutaneous or intramuscular route, according to your doctor’s advice.
Progesterone is routinely given after embryo transfer to support the luteal phase of the treatment cycle and prepare the lining of the uterus to allow an embryo to stick and implant. Progesterone can be taken vaginally as a gel (Crinone), or vaginal tablets (Utrogestan).