Fertility drugs for IVF - in vitro fertilization contain the same hormones that the body normally uses to stimulate eggs to develop in the ovary. These hormones are called gonadotropins. There are two gonadotropins in human beings that stimulate egg development. These two hormones are known as follicle stimulating hormone (FSH) and luteinizing hormone (LH). The amounts of these fertility drugs that are administered in IVF cycles are typically higher than the levels a woman would produce naturally. This hopefully increases the number of eggs that mature and thus multiple eggs will be available for removal and fertilization.
The newest types of gonadotropins are made from recombinant DNA technology and include Gonal F and Follistim. Gonal F and Follistim contain the most highly purified preparation of FSH possible. The older versions of gonadotropins are isolated from the urine of post-menopausal women and include those which contain FSH and LH such as Pergonal, Repronex, Humegon, and Menopur, and those contain mostly FSH such as Fertinex, Metrodin and Bravelle. All of these medications are expensive.
Cetrotide and Ganirelix (Antagon) in IVF
Cetrotide (cetrorelix) and ganirelix (Antagon) are examples of a type of medication that is used to prevent premature ovulation. This class of medications is referred to as GnRH antagonists or simply antagonists. Cetrotide and Antagon are newer medications than Lupron but have become tremendously popular as a result of their ease of use and high pregnancy rates.
Medications which work rapidly
Cetrotide and Ganirelix exert their action on the pituitary gland. The pituitary is responsible for producing the hormones which stimulate egg growth and development and for triggering ovulation of a mature egg. During an in vitro fertilization cycle, the physician needs to prevent ovulation from occurring so the eggs can be removed directly from the ovary.
In the early days of IVF, before medications to prevent ovulation were available, about 25% of IVF cycles would be cancelled for premature ovulation. Then a medication called Lupron (Differelin)was used to block the pituitary from causing premature ovulation. Lupron caused a few problems, however. When Lupron is first administered to a woman, it would stimulate her pituitary gland for several days before it would eventually suppress it. This is known as the stimulation or flare phase. The flare phase required that women start Lupron a few weeks before she could begin the fertility medications required for stimulation of the ovary. In some women, the flare effect can cause the development of cysts in the ovaries that could further delay the start of fertility medications.
A primary advantage of Cetrotide and Ganirelix is that they do not have a "flare phase". Down regulation (suppression) of the pituitary occurs immediately. Therefore, it is not necessary to start these medications before the fertility medications begin .Cetrotide or Ganrelix would normally be started after 4-6 days after the start of the fertility medications. This shortens the number of days that a woman must take injections.
There are two protocols for beginning the Cetrotide or Ganirelix. One method, called the flexible start, utilizes the results of the blood and ultrasound monitoring of egg development. Once development of the eggs has started to occur, the Cetrotide or Ganirelix is started. A second method, called the fixed start, will begin the Cetrotide and Ganirelix after a certain number of days of fertility medication have been given regardless of the results of blood and ultrasound monitoring.
The GnRH antagonists are continued along with the fertility medication until the last day of fertility medication is given. Typically this means a woman will have 4-6 days of Cetrotide or Ganirelix before the egg retrieval.
Some experts believe that IVF cycles that use Lupron for pituitary suppression, may cause some women to become "over-suppressed" and therefore not respond as well to the fertility medications.
Lupron treatment in IVF
Lupron has several possible uses in assisted reproduction:
How does Lupron work?
as the trigger injection prior to egg retrieval to reduce the risk of hyperstimulation
as part of the "flare" protocol to help women who respond poorly to fertility medications.
suppression of the pituitary to prevent ovulation
Lupron(Differelin) acts by suppressing the pituitary gland (the gland which is normally responsible for triggering ovulation). However, before suppression occurs, Lupron will briefly stimulate the pituitary causing an increase in the pituitary hormones LH (luteinizing hormone) and FSH (follicle stimulating hormone). This is called the agonist or flare phase . If the Lupron is continued, it will eventually stop the pituitary from producing LH and FSH. This is known as the suppression phase.
Since it requires an extended period time to reach the suppression phase, Lupron is usually started a few weeks before starting the other medications needed for a particular treatment. This allows the patient to "get past" the stimulation phase and into the suppression or desensitization phase.
During the suppression phase, spontaneous ovulation will not occur. You may hear the staff refer to the patient during this phase as being "down-regulated" or "suppressed". This suppression effect will even persist for a few weeks after the Lupron is stopped.
Today, Lupron suppression is used primarily for frozen embryo transfer cycles and egg donation cycles. Some programs may still use Lupron for fresh IVF cycles .
The flare effect of Lupron can be used at the beginning of a fresh IVF cycle to help stimulate the development and maturation of eggs. Lupron is given for a few days and then injectable fertility medications are started. The flare protocol is rarely used anymore since it does not appear to produce any benefit over other simpler protocols.
The "flare effect" of Lupron can also be used at the end of an IVF stimulation in place of the hCG trigger injection. This use of Lupron is primarily reserved for women who have responded too vigorously to the fertility medications and are at risk for ovarian hyperstimulation syndrome.
Method for using Lupron
Because the flare phase can sometimes result in annoying problems like the development of ovarian cysts, we try to minimize he occurrence of those problems by starting the Lupron in one of two ways:
Lupron can be started after ovulation has occurred. If a woman has a 28 day menstrual cycle, she would normally ovulate around Day 14. Lupron would be started by checking a blood test to verify ovulation (progesterone level) between the 18th and 25th day. If ovulation were verified, the Lupron would then be started.
Using birth control pills
The problems with Lupron can also be reduced by first starting a woman on birth control pills. The pills can be given for variable lengths of time but at least for 10 days. The Lupron can be started at any point after the fifth day. Once started, the birth control pills would be continued for five additional days and then stopped.
Once a patient achieves pituitary suppression, she will sometimes get a period, but not always. Therefore, in order to verify pituitary suppression, we will have the patient come to the office for a blood test and ultrasound. We will ask the patient to call us to schedule this appointment if she gets a period while on the Lupron but in any case if she has taken two weeks of Lupron.
The hCG trigger injection is one of the most critical parts of the IVF medication protocol. After the eggs have been stimulated to grow and develop, the hCG trigger is the final medication given before the egg retrieval.
IVF hCG Trigger
The hCG trigger has several functions:
If an egg retrieval was not performed, or if it was not performed on time, the hCG trigger would eventually cause ovulation to occur. Therefore, the egg retrieval is performed at a very specific time. At IVF, we like to perform the retrieval as close as possible to 36 hours after the hCG trigger is given.
- Induce final maturation of the eggs
- Cause the resumption of meiosis
- Loosen the egg's attachment from the follicle wall
- Allow for the timing of the egg retrieval
The levels of hCG that get into the bloodstream are affected by the dose of hCG given and the weight or body mass of the woman taking it. Heavier women have lower hCG levels than lighter women even if they take the same dose. For this reason, we alter the dose of the hCG trigger based on the body mass index of the woman.
hCG is available as two different types of medication:
- Urinary hCG - Is derived from the urine of pregnant women. Brand names include Pregnyl, Profasi, Novaryl or generic :chorionic gonafotropins for injection"
- Recombinant hCG - Is produced using recombinant DNA technology. The only brand available is called Ovidrel
Progesterone is made from the ovaries after ovulation. During IVF cycles, progesterone is produced after the hCG trigger injection is taken. Using medications to prevent premature ovulation and performing an egg retrieval may cause the progesterone production to be inadequate. For this reason, we will supplement progesterone. The most reliable way to get progesterone to the uterus is to administer it vaginally. Several studies have been performed comparing vaginal progesterone to intra-muscular injections. In the past, some studies have shown that vaginal progesterone is best whereas some studies showed that intra-muscular progesterone is best. Today, it is almost universally agreed that there is no difference in the chance for pregnancy between the two.