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2. Stimulation Protocolsto "Why does IVF fail?" main page a. General Stimulation Flow SheetOver the past three decades ovarian stimulation has progressed from literally no stimulation with a natural cycle to the use of potent gonadotropins that induce the production of multiple eggs. Additionally, medicines the will inhibit the natural tendency to ovulate (i.e. GnRH agonists and antagonists) have led to even more control of the cycle and more precise timing and improved outcomes. While a detailed discussion of the history of ovarian stimulation is beyond our goal here, I will try and show patients how a typical IVF stimulation progresses. Other pages on our site show the basic stimulation protocol (i.e., see PDF file IVF Long Lupron Protocol) which the following flow sheet corresponds to. Most REI physicians will have a flow sheet (Figure 6, below) summarizing the ultrasounds and blood work (i.e. Estradiol, LH, and Progesterone) for the IVF cycle. When we look at the stimulation flow sheet we can see certain important things that may influence our management of the IVF stimulation. Please see the example below. During a stimulation, several events may occur. For instance, in the long Lupron protocol below, a patient may start the Lupron on cycle day 21 of the month preceding the stimulation. The patient generally will start her menses around the 10th day of the Lupron as seen on the example. Some patients may not start the cycle as predicted. We sometimes refer to this as being ‘too suppressed’. It is likely the stimulation will not progress well so we may cancel the cycle. At the baseline ultrasound on days 1-3 of the stimulation, we check to see if there are any ovarian cysts. Sometimes Lupron will cause patients to have cyst formation and this may lead to cancellation. Lupron 1st stimulates the pituitary and then suppresses it, and it may be that the luteal stimulation phase causes these cysts. We also check the baseline estrogen level. It if is too high (i.e. 100 pg/ml) on this type of protocol we may need to cancel because of inadequate suppression. The LH and progesterone levels also tell us of the extent of ovarian suppression. We generally have the patients in on the 5th day of gonadotropin medication. Here we are expecting to see a cohort of follicles growing, generally in the 10 mm to 12 mm range. If the estrogen level is very low, a cycle may be cancelled as well. It again means that the patient was ‘too suppressed.’ Every two days later we expect to see the estradiol levels double and a corresponding increase in follicle size. When they reach the appropriate size, generally greater than 18mm, and the estradiol, LH and progesterone are appropriate. We often hope to have one healthy egg for every 200 pg/ml to 250 pg/ml of estradiol. When a cycle fails, the REI may review the flow sheet and put it into the context of the eggs and embryos that were obtained. Often we can change the protocol to significantly to get a better outcome. There is no one stimulation that works best for all patients which is understandable given the many different patients we see. There is an ‘ART’ to IVF stimulations! Figure 6. Sample ovulation induction flow sheet.
b. Long versus Short LupronAs noted above, Lupron is a gonadotropin releasing hormone agonist (GnRH-a).
An agonist is a drug that binds a natural hormone receptor and elicits a
response similar to the natural ligand. GnRH is secreted by the
hypothalamus of the brain and acts on the pituitary gland to cause the
secretion of FSH and LH in a pulsatile fashion. When a patient takes
Lupron the drug 1st stimulates the secretion of FSH and LH and then
suppresses their secretion. This may take about 7-10 days. Thus the
medicine is sometimes administered on day 21 of the cycle before the
ovarian stimulation or it is taken when birth control pills are used.
Lupron may cause ovarian cysts formation, so BCPs may be used in the
protocol to help decrease cyst formation. Basically, we are using Lupron
to block the hormonal communication between the ovaries and their control
center at the pituitary and hypothalamus. By blocking the natural tendency
for ovulation (i.e. LH release) to occur, we are able to super stimulate
the ovaries to produce many more eggs. The ‘long protocol’ is often used
as a first line therapy. c. AntagonistsAn antagonist is a drug that occupies a receptor but has no action. In the case of GnRH, the drug binds the GnRH receptors on the anterior pituitary but does not elicit the release of FSH and LH. These drugs (i.e., Antagon, Ganirelix) act very quickly after a subcutaneous dose. They are typically begun during the gonadotropin stimulation once the follicles are >14 mm is size. It is possible that the administration of the drug when the follicles are smaller may slow the stimulation. Regardless, patients may have a drop in estradiol levels with the administration of the antagonist and some protocols call for increasing the gonadotropin stimulation when the antagonist is used. There are some patients that may do well with this type of stimulation and it is utilized by many programs. d. FSH vs HMGOvarian stimulation is primarily accomplished with the gonadotropin medications. They are either derived from highly purified menopausal urine (HMG, Human Menopausal Gonadotropins; Repronex, Menopur) or synthesized through recombinant DNA technology (Gonal-f, Follistim). Ultimately one may not be better than the others for all patients. The drugs have different actions to some degree and this can be exploited in different protocol. For instance, in the long Lupron protocol, both FSH and LH may be suppressed significantly. The LH acts on the theca cells that surround the ovarian follicle and stimulate the production of androgen hormones which cross into the follicle and act as substrates for estradiol production via the action of FSH on the follicle granulosa cells. In a way, the LH acts to prime the estrogen producing pump. The use of HMG provides LH as well as FSH. If a pure FSH medication is used, we many need to add LH back in the form of recombinant LH (i.e., Luvoris) or HCG. The HMG preparations have 75 IU FSH, 75 IU LH, and a small amount of HCG. Some patients may not need the extra LH, so pure FH may be used. In many ways, trial and error, prior responses, and physician experience play a huge role in the choice of protocol. e. Premature LuteinizationPremature luteinization is a phenomenon where progesterone levels rise in the serum before the normal post ovulatory period. In the normal menstrual cycle, the LH surge induces ovulation and then LH stimulates the corpus luteum to produce progesterone which is required for normal implantation. The uterine lining goes through a specific series of changes in response to progesterone when it develops during the ‘implantation window.’ Premature luteinization has been suggested when the progesterone levels rise above 2 ng/ml. Some, but not all, studies have shown that the pregnancy rates are lower when the progesterone levels rise. This may affect implantation and may not be due to an increase in LH. Sometimes, when we ‘coast’ the over stimulated patient, premature luteinization may occur and this may be responsible for the lower implantation rate seen in some patients that coast >4 days. Many programs monitor the LH and progesterone levels to assess the stimulation for evidence of premature luteinization. f. Fluid in uterine cavity during stimulationDuring the IVF stimulation ultrasonography is used to monitor the follicle growth and to assess the uterine lining. Often we see a tri-laminar uterine lining where the anterior and posterior walls come together in the midline. This tri-layered appearance has been associated with good uterine blood flow and implantation. A homogenous pattern may not be as good with respect to the implantation rates. In a very small number of patients, and actual fluid collection is seen during the stimulation. This may be seen in patients that are very over-stimulated or under-stimulated, patients with hydrosalpinges (blocked tubes and fluid going back into cavity), or patients that may have a sub-clinical uterine infection. The pre-op HSG should rule out any tubal factor. Regardless of the cause, and there is no uniform consensus about the exact mechanism, the pregnancy rates are lower when this fluid is seen. The options include cancellation of the cycle outright and switching to a different protocol, or obtaining the eggs and freezing the embryos. Some have suggested using a small catheter to aspirate the fluid and still do the transfer, but it may accumulate and affect implantation. An example is shown in Figure 7. Figure 7. Fluid in endometrial cavity on day #7 of stimulation
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