At SIRM we prescribe leuprolide acetate (Lupron) to launch most IVF controlled ovarian hyperstimulation (COH) cycles. Lupron is very similar in structure to GnRH. As such, its initial effect (for about 2-4 days or so) is to stimulate the pituitary gland to produce both LH and FSH. As soon as the pituitary starts to recognize the difference in chemical structure between the Leuprolide and normal GnRH, it profoundly reduces its output of biologically active LH and FSH production. This is referred to as “pituitary down-regulation” and the effect continues for as long as Lupron therapy is maintained uninterrupted. The initial increase in FSH and LH production during the first 4-6 days of leuprolide therapy is accompanied by a transient, but very significant increase in estrogen release by the ovary. The initial rise in LH and FSH production results in a rise in estradiol, and the subsequent pituitary “down-regulation” is followed by a precipitous fall in blood estrogen levels, until gonadotropin or estrogen administration commences.
The reason that agonists are administered to women receiving Gonadotropin therapy for IVF is because of its ability to suppress LH and so prevent a premature rise in LH which is most likely to occur in older women or those with have diminished ovarian reserve. When this happens the cells lining the follicles undergo premature change (premature luteinization), compromising further follicle development and egg/embryo quality. Such premature luteinization (previously referred to as “premature LH surge”) severely compromises further follicle development as well as egg/embryo quality. Women with reduced ovarian reserve (who are resistant to ovarian stimulation) are most susceptible to this happening.
There is often talk of agonists “over-suppressing” ovarian response to gonadotropins. The reason for this concern is that agonists probably compete with FSH for receptor binding sites on the granulosa cells that line the ovarian follicles and produce estrogen…and so can blunt ovarian follicle response to FSH. However, since antagonists apparently do not exert the same effect, by supplanting Lupron with an antagonist prior to starting gonadotropin therapy, avoids this problem (see the agonist/antagonist conversion protocol -A/ACP below). While both antagonists and agonists block LH activity, antagonists do so much more rapidly (within hours) than agonists (within a few days).
Use of Lupron to Launch COH for IVF
At SIRM we launch COH for IVF by putting the woman on a birth control pill (BCP) for 10-25 days, to suppress ovarian response to FSH/LH. Thereupon, Lupron is overlapped with the BCP for 2-4 days. Then the BCP is discontinued and daily Lupron therapy is continued until menstruation ensues. By varying the length of time on Lupron it is possible to control the timing of the onset of menstruation and reduce the incidence of cycle cancellation due to ovarian cyst formation. Menstruation will usually occur 4-7 days after stopping the BCP. Thereupon, one of two variations in approach is taken. Either the long Lupron approach or the agonist/antagonist conversion protocol (A/ACP) is used. With the A/ACP, Lupron is supplanted by low dosage antagonist therapy. In both cases, daily Gonadotropin (FSH and LH) injections are concomitantly initiated and continued with the agonist or antagonist until the day of the hCG trigger.
In some cases of markedly diminished ovarian reserve, we preempt the initiation of gonadotropin therapy with “estrogen priming”. It involves twice weekly injections of estradiol valerate for 8-10 days and then we initiate Gonadotropin therapy which is continued until more than 50% of the developing follicles reach at least 12mm in diameter. The addition of estrogen in this way is believed to improve ovarian response to gonadotropins as well as endometrial response to estrogen stimulation. In both the long Lupron approach and the A/ACP, daily shots of antagonist or antagonist are continued up to the day of the hCG trigger. The egg retrieval (ER) is performed 35-37 hours following hCG administration.
Lupron Use in Embryo Recipient Cycles
Cases of egg donation, embryo donation, gestational surrogacy, and frozen/thawed embryo transfers (FET) undergo a similar regime of BCP/agonist preparation as do those who undergo ovarian stimulation, except that instead of receiving gonadotropin injections, these women receive daily estradiol valerate injections. Thereupon, progesterone therapy (administered by intramuscular injection and/or by vaginal administration) is added for several days. The combination of estrogen and progesterone therapy prepares the uterine lining for embryo implantation. Lupron therapy is discontinued 5-7 days prior to Embryo Transfer (ET) in such cases.
There is really no need to be overwhelmed by what at first might seem to be a complex treatment regimen. Extensive studies on non-human primates, as well as limited human evaluations, indicate that Lupron is relatively harmless to both mother and baby. The drug is eliminated from the system within hours of discontinuing its administration. At SIRM we discontinue Lupron therapy at least 5-7 days prior to transferring embryos/blastocysts to the woman's uterus. The administration of subcutaneous or trans-nasal agonist is rarely associated with significant side effects. Some women experience temporary fluctuations in mood, hot flashes, nausea, and symptoms not similar to PMS. No serious long-lasting side-effects have been reported.
The subcutaneous injection of Lupron is relatively painless. Unfortunately, the drug will incur a modest additional financial burden. Lupron administration as described above spares women the inconvenience and frustration of unnecessary cancelled treatment cycles with gonadotropins. As such, the use of Lupron in reality reduces the overall cost of ovulation induction.
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