Agonist (Lupron) Therapy in IVF

Dr. Geoffrey Sher - August 22, 2018
Agonist (Lupron) Therapy in IVF

All gonadotropin releasing hormone (GnRH) agonists act by rapidly expunging reservoirs of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. GnRH agonists can be administered by intramuscular injection (e.g. Lupron, Buserelin) or through intranasal administration (Nafarelin, Synarel). The intramuscular route which insures more even absorption is preferred.

At Sher-IVF we prescribe leuprolide acetate (Lupron) to launch moist IVF-controlled ovarian hyperstimulation (COH) cycles. Lupron is very similar in structure to gonadotropin releasing hormone (GnRH) . As such, its initial effect, (for about 2-4days 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 is below). While both antagonists land s block LH activity, antagonists do so much more rapidly (within hours) than agonists (within a few days).

Risks associated with taking  Lupron,  short periods of time in IVF, are in my experience rare and side effects are mild. Long term use (especially when depot-Lupron is administered)  is another matter altogether. In fact people who take Lupron for long periods are more prone to certain health risks. They include changes in heart rhythm and electrical signals in the heart, slow heartbeat, congestive heart failure, heart attack, and bone softening. As such, I never prescribe long term Lupron usage to my IVF patients.

Use of Lupron to launch Ovarian Stimulation for IVF: At Sher-IVF we launch controlled ovarian stimulation (COS) 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 thee 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 reduces 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 Gonadotropins 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 could 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.

Some clinicians, when faced with the risk of OHSS developing will deliberately elect to reduce the dosage of hCG administered as a trigger in the hope that by doing so the risk of critical OHSS developing will be lowered.  It is my opinion, that such an approach is not optimal because a low dose of hCG (e.g., 5000 units, hCGu or 250mcg hCGr) is likely inadequate to optimize the efficiency of egg maturational division (meiosis), particularly when it comes to cases such as this where there are a large number of developed follicles.

Lupron (Agonist) “Flare (Short” Protocol: Some IVF physicians advocate the use of GnRHa (Lupron)- flare protocols in which the administration of Lupron, therapy begins at the same time that ovarian stimulation with gonadotropins is started (usually with the onset of menstruation). The proposed benefit of such an approach is that the GnRHa will cause the woman’s pituitary gland to release large amounts of follicle stimulating hormone (FSH), which would augment the administered dosage of FSH and thereby synergizing the growth of ovarian follicles. The problem associated with this “flare” approach is that concurrent with the GnRHa-induced FSH luteinizing hormone (LH) also surges. In older women and those who have diminished ovarian reserve, the out-pouring of LH can cause the ovarian connective tissue (stroma or theca) which produces excessive male hormones (predominantly, testosterone). While some testosterone is essential for optimal follicle growth, too much testosterone can compromise its development as well as egg/embryo quality. Since older women and women with diminished ovarian reserve often have increased LH production as well as an overgrown of ovarian stroma/theca (i.e. hyperthecosis), a further GnRHa-induced increase in LH can so elevate local ovarian testosterone levels as to severely compromise egg/ embryo “competency”.

The Lupron (Agonist) “trigger”: It has been suggested that the preferential use of an “agonist (Lupron) trigger” in women at risk of developing severe ovarian hyperstimulation syndrome (OHSS) could potentially reduce the risk of the condition becoming critical and thereby placing the woman at risk of developing life-endangering complications. The argument is that the Lupron “trigger” by causing an LH surge to occur will reduce the risk of severe complications due to OHSS. The problem with using this approach, in my opinion, is that it is hard to predict how much LH will be released in by the pituitary gland. Often times, the magnitude of the LH surge induced by Lupron, is not sufficient to promote maximum and orderly egg maturation in the 36-38 hours prior to egg retrieval. The result is that eggs are more likely to be chromosomally irregular (aneuploid) when the Lupron “trigger” is used. So, in my opinion, while the Lupron “trigger” might well reduce the severity of OHSS-related complications, this benefit often comes at the expense of egg/embryo quality and outcome.   For this reason, I personally prefer to use hCG for the trigger, even in cases of ovarian hyperstimulation hyperstimulated, with one important proviso…that being that is she underwent “prolonged coasting” in order to reduce the risk of critical OHSS, prior to the 10,000-unit hCGu “trigger”.

Lupron use in embryo recipient cycles: In cases of egg donation and gestational surrogacy, embryo donation and with frozen/thawed thawed embryo transfers (FET) undergo a similar regime of BCP/agonist preparation as do those who undergo ovarian stimulation, except that instead of receiving gonadotropins 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 little need to be alarmed at 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 Sher-IVF 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 vastly dissimilar from 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 (for ovarian stimulation), 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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