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).

Use of Lupron to launch COS 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

2 Comments

Shehrezad

Hi Dr. My husband and I have been to several fertility doctors in our area and a few have recommended using Lupron for two months to treat my endometriosis prior to doing our transfer using banked embryos. We have been told this cuts estrogen supply which helps control endometriosis enough to transfer. Wondering from your perspective if there is a down side to this approach? We were told to be on Lupron for two months. Then to let it completely exit my system and then we would be put on the regular protocol for transferring our embryo. Our embryo has been PGS approved and vitrified. Do you think this approach is optimal?

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Dr. Geoffrey Sher

Very respectfully, I do not agree! First, as soon as the Lupron is stopped, the endometriosis will immediately start returning. Second, endometriosis affects the outside of the uterus and wont affect the endometrium. Third, long term Lupron will create a hypoestrogenic effect on the endometrium which can down-regulate the estrogen receptors so that when you then get hormone therapy, the endometrium might not be able to adequately respond to estrogen.

I recommend that you carefully review the information below and then perhaps we should talk.

Endometriosis is a condition that occurs when the uterine lining (endometrium) grows not only in the interior of the uterus but in other areas, such as the fallopian tubes, ovaries and the bowel. Endometriosis is a complex condition where, the lack or relative absence of an overt anatomical barrier to fertility often belies the true extent of reproductive problem(s).

All too often the view is expounded that the severity of endometriosis-related infertility is inevitably directly proportionate to the anatomical severity of the disease itself, thereby implying that endometriosis causes infertility primarily by virtue of creating anatomical barriers to fertilization. This over-simplistic and erroneous view is often used to support the performance of many unnecessary surgeries for the removal of small innocuous endometriotic lesions, on the basis of such “treatment” evoking an improvement in subsequent fertility.

It is indisputable that even the mildest form of endometriosis can compromise fertility. It is equally true that, mild to moderate endometriosis is by no means a cause of absolute “sterility”.

Rather, when compared with normally ovulating women of a similar age who do not have endometriosis, women with mild to moderate endometriosis are about four to six times less likely to have a successful pregnancy.

Endometriosis often goes unnoticed for many years. Such patients are frequently, erroneously labeled as having “unexplained infertility”, until the diagnosis is finally clinched through direct visualization of the lesions at the time of laparoscopy or laparoscopy. Not surprisingly, many patients with so called “unexplained” infertility, if followed for a number of years, will ultimately reveal endometriosis.

Women who have endometriosis are much more likely to be infertile. There are several reasons for this:

• First-Ovulation Dysfunction: In about 25 – 30% of cases, endometriosis is associated with ovulation dysfunction. Treatment requires controlled ovarian stimulation (COS). The problem is that the toxic pelvic environment markedly reduces the likelihood that anything other than IVF will enhance pregnancy potential.
• Second- Toxic Pelvic environment that compromises Fertilization Endometriosis is associated with the presence of toxins in peritoneal secretions while it is tempting to assert that normally ovulating women with mild to moderate endometriosis would have no difficulty in conceiving if their anatomical disease is addressed surgically or that endometriosis-related infertility is confined to cases with more severe anatomical disease…nothing could be further from the truth. The natural conception rate for healthy ovulating women in their early 30’s (who are free of endometriosis) is about 15% per month of trying and 70% per year of actively attempting to conceive. Conversely, the conception rate for women of a comparable age who have mild or moderate pelvic endometriosis (absent or limited anatomical disease) is about 5-6% per month and 40% after 3 years of trying. As sperm and egg(s) travel towards the fallopian tubes they are exposed to these toxins which compromise the fertilization process. In fact it has been estimated that there is a 5-6 fold reduction in fertilization potential because of these toxins which cannot be eradicated. Frankly, it really does not matter whether an attempt is made to remove endometriosis deposits surgically as this will not improve pregnancy potential. The reason is that for every deposit observed, there are numerous others that are in the process of developing and are not visible to the naked eye and whether visible or not, such translucent deposits still produce toxins. This also explains why surgery to remove visible endometriosis deposits, controlled ovarian stimulation with or without intrauterine insemination will usually not improve pregnancy potential. Only IVF, through removing eggs before they are exposed to the toxic pelvic environment, fertilizing them in-vitro and then transferring the embryos to the uterus represents the only way to enhance pregnancy potential.
• Third-Pelvic adhesions and Scarring: In its most severe form, endometriosis is associated with scarring and adhesions in the pelvis, resulting in damage to, obstruction or fixation of the fallopian tubes to surrounding structures, thereby preventing the union of sperm and eggs.
• Fourth-Ovarian Endometriomas, Advanced endometriosis is often associated with ovarian cysts (endometriomas/chocolate cysts) that are filled with altered blood and can be large and multiple. When these are sizable (>1cm) they can activate surrounding ovarian connective tissue causing production of excessive male hormones (androgens) such as testosterone and androstenedione. Excessive ovarian androgens can compromise egg development in the affected ovary (ies) resulting in an increased likelihood of numerical chromosomal abnormalities (aneuploidy) and reduced egg/embryo competency”. In my opinion large ovarian endometriomas need to be removed surgically or rough sclerotherapy before embarking on IVF.
• Fifth- Immunologic Implantation Dysfunction (IID). Endometriosis, regardless of its severity is associated with immunologic implantation dysfunction linked to activation of uterine natural killer cells (NKa) and cytotoxic uterine lymphocytes (CTL) in about 30 of cases. This is diagnosed by testing the woman’s blood for NKa using the K-562 target cell test or by endometrial biopsy for cytokine analysis, and, for CTL by doing a blood immunophenotype. These NKa attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in death of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or even an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.

Advanced Endometriosis: In its most advanced stage, anatomical disfiguration is causally linked to the infertility. In such cases, inspection at laparoscopy or laparoscopy will usually reveal severe pelvic adhesions, scarring and “chocolate cysts”. However, the quality of life of patients with advanced endometriosis is usually so severely compromised by pain and discomfort, that having a baby is often low on the priority list. Accordingly, such patients are usually often more interested in relatively radical medical and surgical treatment options (might preclude a subsequent pregnancy), such as removal of ovaries, fallopian pubis and even the uterus, as a means of alleviating suffering.

Moderately Severe Endometriosis. These patients have a modest amount of scarring/ adhesions and endometriotic deposits which are usually detected on the ovaries, fallopian tubes, bladder surface and low in the pelvis, behind the uterus. In such cases, the fallopian tubes are usually opened and functional.

Mild Endometriosis: These patients who at laparoscopy or laparotomy are found to have no significant distortion of pelvic anatomy are often erroneously labeled as having “unexplained” infertility. To hold that the there can only infertility can only be attributed to endometriosis if significant anatomical disease can be identified, is to ignore the fact that, biochemical, hormonal and immunological factors profoundly impact fertility. Failure to recognize this salient fact continues to play havoc with the hopes and dreams of many infertile endometriosis patients.

TREATMENT:
The following basic concepts apply to management of endometriosis-related infertility:

1. Controlled Ovulation stimulation (COS) with/without intrauterine insemination (IUI): Toxins in the peritoneal secretions of women with endometriosis exert a negative effect on fertilization potential regardless of how sperm reaches the fallopian tubes. This helps explain why COS with or without IUI will usually not improve the chances of pregnancy (over no treatment at all) in women with endometriosis. IVF is the only way by which to bypass this problem.
2. Laparoscopy or Laparotomy Surgery aimed at restoring the anatomical integrity of the fallopian tubes does not counter the negative influence of toxic peritoneal factors that inherently reduce the chances of conception in women with endometriosis four to six fold. Nor does it address the immunologic implantation dysfunction (IID) commonly associated with this condition. Pelvic surgery is relatively contraindicated for the treatment of infertility associated with endometriosis, when the woman is more than 35 years of age. With the pre-menopause approaching, such women do not have the time to waste on such less efficacious alternatives. In contrast, younger women who have time on their side might consider surgery as a viable option. Approximately 30 -40 percent of women under 35 years of age with endometriosis will conceive with in two to three years following corrective pelvic surgery.
3. Sclerotherapy for ovarian endometriomas (“chocolate” cysts). About 15 years ago I introduced “sclerotherapy”, a relatively non-invasive, safe and effective outpatient method to permanently eliminate endometriomas without surgery being required. Sclerotherapy for ovarian endometriomas involves needle aspiration of the liquid content of the endometriotic cyst, followed by the injection of 5% tetracycline into the cyst cavity. Treatment results in disappearance of the lesion within 6-8 weeks, in more than 75% of cases so treated. Ovarian sclerotherapy can be performed under local anesthesia or under general anesthesia. It has the advantage of being an ambulatory office- based procedure, at low cost, with a low incidence of significant post-procedural pain or complications and the avoidance of the need for laparoscopy or laparotomy
4. The role of selective immunotherapy More than half of women who have endometriosis harbor antiphospholipid antibodies (APA) that can compromise development of the embryo’s root system (trophoblast). In addition and far more serious, is the fact that in about one third of cases endometriosis, regardless of its severity is associated with NKa and cytotoxic uterine lymphocytes (CTL) which can seriously jeopardize implantation. This immunologic implantation dysfunction (IID) is diagnosed by testing the woman’s blood for APA, for NKa (using the K-562 target cell test or by endometrial biopsy for cytokine activity) and, for CTL (by a blood immunophenotype). Activated NK cells attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in rejection of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.

Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. NKa is treated with a combination of Intralipid (IL) and steroid therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa.

The therapeutic effect of IL/steroid therapy is likely due to an ability to suppress pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha. IL/steroids down-regulates NKa within 2-3 weeks of treatment the vast majority of women experiencing immunologic implantation dysfunction. In this regard IL is just as effective as Intravenous Gamma globulin (IVIg) but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.

5. The role of IVF: The toxic pelvic environment caused by endometriosis, profoundly reduces natural fertilization potential. As a result normally ovulating infertile women with endometriosis and patent Fallopian tubes are much less likely to conceive naturally, or by using fertility agents alone (with or without intrauterine (IUI) insemination. The only effective way to bypass this adverse pelvic environment is through IVF. I am not suggesting here that all women who have endometriosis require IVF! Rather, I am saying that in cases where the condition is further compromised by an IID associated with NKa and/or for older women(over 35y) who have diminished ovarian reserve (DOR) where time is of the essence, it is my opinion that IVF is the treatment of choice.

I strongly recommend that you visit http://www.SherIVF.com . Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements for Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; hHow it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
• Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF.
• Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
• Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
• Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
• Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination-IUI) and Reproductive Surgery Versus IVF
• Treating Ovarian Endometriomas with Sclerotherapy.
• Effect of Advanced Endometriosis with Endometriotic cysts (Endometriomas) on IVF Outcome & Treatment Options.
• Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
• Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s &
• Induction of Ovulation with Clomiphene Citrate: Mode of Action, Indications, Benefits, Limitations and Contraindications for its use
• Clomiphene Induction of Ovulation: Its Use and Misuse!
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ADDENDUM:
INTRODUCING SHER FRERTILITY SOLUTIONS (SFS)
Hitherto I have personally performed the actual hands-on treatment of all patients who, seeking my involvement, elected to travel to Las Vegas for my care. However, with the launching of Sher-Fertility Solutions (SFS), I will as of March 31st take on a new and expanded consultation role. Rather than having hands-on involvement with IVF procedures I will, through SFS, instead provide fertility consultations (via SKYPE) to the growing number of patients (from >40 countries) with complex Reproductive Dysfunction (RD) who seek access to my input , advice and guidance. In this way I will be able to be involved in overseeing the care, of numerous patients who previously, because they were unable to travel long distances to be treated by me, were unable to gain access to my input.

Anyone wishing to schedule a Skype consultation with me, can do so by: Calling my concierge (Patti Converse) at 1-800-780-7437 for an appointment,enrolling online on my website, http://www.SherIVF.com, or 702-533-2691; or emailing Patti at concierge@SherIVF.com or . sher@sherivf.com .
I was very recently greatly honored in receiving an award by the prestigious; International Association of Top Professionals (IAOTP). For more information, go to the press release on my website, http://www.sherIVF.com .

PLEASE HELP SPREAD THE WORD ABOUT SFS!

Geoff Sher

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