Controlled Ovarian Stimulation
A woman’s eggs develop inside fluid-filled sacs inside the ovaries called follicles. During a natural menstrual cycle in which no fertility drugs are taken, several follicles begin to enlarge around the time when the woman is having her period.
However, over the course of the next few weeks, only one or at most two of these eggs develops to maturity, at which time the follicle ruptures, and releases its egg during the process of ovulation. The other follicles that had begun to develop stop growing and become atretic (degenerate). Therefore, only a small percentage of eggs present in the ovaries are ever released to have the potential for fertilization and pregnancy during the woman’s reproductive life span.
Ovarian Stimulation During IVF
During the in vitro fertilization (IVF), we typically try to obtain as many mature eggs as possible since even in the best of circumstances, not every egg typically fertilizes, results in an embryo that develops appropriately and is genetically normal. A variety of fertility drugs, which contain FSH (follicle stimulating hormone) are administered to try to accomplish this task. This is the same hormone that the pituitary gland produces to cause one egg to develop. By increasing the woman’s blood level of FSH, several follicles may grow at approximately the same rate allowing us to collect more than one mature egg.
It is important to remember that we do not create new eggs, but rather, rescue eggs that would otherwise not have been used. The number of eggs that can be obtained can typically be estimated as part of the initial fertility evaluation during an ultrasound evaluation, which includes a measurement of the antral (resting) follicle count that portrays the number of eggs which are available in a given month. This number varies a bit from month to month and declines over a woman’s reproductive life span.
Personalized Ovarian Stimulation Protocols
CCRM has developed a variety of protocols that are individualized to each patient and will be provided by your physician after a thorough evaluation has been completed. Important characteristics that are taken into account include age, past history, ovarian reserve testing results (FSH, estradiol, AMH levels), and antral follicle count.
There are several classes of medications that are typically used as part of the stimulation process. It is important to remember that not all of these agents are given as part of every protocol. Most of the medications can be self administered as small injections under the skin (subcutaneous injections).
Priming or preparation
A variety of agents are given in the weeks before stimulation of the ovaries starts. These are designed to either improve ovarian response and to create more symmetrical growth of the follicles and maturity of the eggs. This may include oral contraceptives or oral estrogens and occasionally testosterone as will be indicated by the specific protocol determined by your CCRM physician.
These are a variety of medications that stimulate the maturity of the resting follicles and represent higher levels of the hormones FSH and possibly LH (luteinizing hormone) which allow more than one egg to develop. Initial dosing is individualized to each patient and doses are adjusted based on evaluation of hormone levels through blood tests and ultrasound examinations which reflect the growth of the follicles and maturation of eggs. Currently available agents in the United States have the trade names of Gonal-F, Follistim and Menopur. The length of time of administration varies for each individual but typically an average duration is 9-12 days.
One of the concerns with ovarian stimulation is that a woman could ovulate prematurely, which means that the eggs cannot be retrieved. One of two classes of medications are typically given to prevent this from happening. The first class of medicines are call GnRH agonist. The agent most typically used in the United States is leuprolide acetate (Lupron and generics). Lupron causes the pituitary gland to release high amounts of FSH and LH (luteinizing hormone) for several days until its stores are depleted. Since continued use of Lupron prevents the pituitary gland from producing new supplies of FSH and LH, the amount of these hormones being released per day becomes very low after 7 to 10 days. The goal of Lupron is to ensure that blood levels of LH are low during the last few days of follicle growth. High levels of LH can lead to poor egg quality, premature ovulation, and stimulate progesterone production by the ovaries. A premature rise in progesterone may cause inappropriate maturation of the uterine lining and lead to lower chances of embryo implantation. Younger women or those with polycystic ovaries are usually treated with Lupron for approximately 10 days prior to beginning the shots of FSH. With this “long Lupron” schedule, the pituitary is no longer releasing large amounts of LH and FSH when gonadotropins are started. Some women will be placed on a Lupron “flare” medication schedule. This involves starting Lupron early in the menstrual cycle after suppressing pituitary and ovarian function for up to one month of birth control pills. The Lupron causes a rapid increase in FSH and LH release by the pituitary gland and initiates follicular growth but over time also suppresses ovulation. On the third day after the Lupron starts, the woman begins shots of gonadotropins to stimulate the continued growth of the follicles as the pituitary’s release of FSH begins to decline.
Another class of drugs called gonadotropin releasing horomone (GnRH) antagonists (with brand names in the United States of ganirelix or Cetrotide) has been used more commonly in our protocols in that they cause a rapid suppression of a spontaneous LH surge and ovulation without overly suppressing ovarian function. These medications are typically not administered until after ovarian stimulation is well underway.
Once the follicles have grown sufficiently, estradiol levels have risen appropriately, ovulation is triggered by one of two means. One approach is to be administered a shot of hCG (human chorionic gonadotropin). This is the hormone of pregnancy, but has a lot in common structurally with the hormone LH and, therefore, can induce ovulation. A second approach is to actually give Lupron to patients who are taking cetrotide or ganirelix as part of their protocol. This makes the pituitary gland release its own stores of LH to cause ovulation. This latter approach has been shown to significantly reduce the risk of ovarian hyperstimulation syndrome in women who have very high estradiol levels. In some protocols, both agents are given. These agents typically induce ovulation 36-44 hours after administration. Therefore, the oocyte aspiration (egg retrieval) procedure is usually scheduled for 35 hours after these medications are given. Your physician will discuss the rationale behind which approach best suits your individual needs.