IVF – Double Trigger – The 411

baby - trigger shot

** Credit:  http://www.ovarianresearch.com

Co-administration of GnRH-agonist and hCG for final oocyte maturation (double trigger) in patients with low number of oocytes retrieved per number of preovulatory follicles-a preliminary report

Abstract

Background

Recently, the co-administration of GnRH agonist and hCG for final oocyte maturation- 40 and 34 hours prior to OPU, respectively (double trigger) was suggested as the treatment of genuine empty follicle syndrome. In the present study, we aim to evaluate whether the double trigger improves the number of oocytes retrieved in patients with low (<50%) number of oocytes retrieved per number of preovulatory follicles.

Methods

In this proof of concept cohort historical study, we compared the stimulation characteristics of 8 IVF cycles, which include the double trigger to the patients’ previous IVF attempt, triggered with hCG-only.

Results

Patients who received the double trigger (study group) had a significantly higher number of oocytes retrieved, number of 2PN, number of embryos transferred and significantly higher proportions of the number of oocytes retrieved to the number of follicles >10 mm and >14 mm in diameter on day of hCG administration, with a tendency toward a higher number of TQE, as compared to their previous cycles (hCG-only trigger). Three ongoing clinical pregnancies were recorded in the study group and none in the hCG-only trigger group.

Conclusions

Co-administration of GnRH-agonist and hCG for final oocyte maturation, 40 and 34 hours prior to OPU, respectively (double trigger), is suggested as a valuable new tool in the armamentarium for treating patients with low/poor oocytes yield despite an apparently normal follicular development and E2 levels and in the presence of optimal hCG levels on the day of OPU.

Keywords:

Oocytes retrieval; GnRH-antagonist; hCG; GnRH-agonist; Final oocyte maturation; IVF outcome

Background

Controlled ovarian hyperstimulation (COH) is considered a key factor in the success of in vitro fertilization-embryo transfer (IVF-ET) because it enables the recruitment of multiple healthy fertilizable oocytes [1]. Moreover, human chorionic gonadotropin (hCG) is usually used at the end of COH, as a surrogate LH surge, to induce final oocyte maturation and resumption of meiosis [2].

Lack of oocyte yield during ovum pick-up (OPU), following COH with an apparently normal follicular development and E2 levels and in the presence of optimal hCG levels on the day of OPU- the genuine empty follicle syndrome (EFS) [3], is a rare entity, with an estimated prevalence of 0–1.1% [4,5]. On the other hand, a more frequently encountered situation is the normally responding patients with a low oocytes yield, i.e. a low ratio (<50%) between the number of oocytes retrieved to the number of follicles >14 mm in diameter on the day of hCG administration.

Despite many years of clinical experience [6], the underlying mechanism of the aforementioned conditions is still obscure and no precise prevention methods exist [5]. Several strategies were offered to patients with EFS [summarized in [5]], including another standard ART cycle; shifting from an GnRH-agonist to GnRH-antagonist COH protocol; re-administering hCG from a different batch and aspirating the second ovary; changing the hCG from a urinary to a recombinant preparation; using GnRH-agonist for final; prolonging the interval between ovulation triggering and OPU; and follicle flushing during oocyte retrieval [7].

Recently, a new treatment modality has been clinically implemented to EFS patient, with the co-administration of GnRH agonist and hCG for final oocyte maturation- 40 and 34 hours prior to OPU, respectively (double trigger) [5]. This method combines the advantage of both: (1) the prolongation of the time between ovulation triggering and OPU; and (2) the GnRH agonist trigger with the consequent simultaneous induction of an FSH surge.

Prompted by this new remedy, we offered the double trigger to all our patients, who underwent the GnRH-antagonist COH protocol, resulting with poor oocytes yield due to low (<50%) number of oocytes retrieved per number of follicles > 14 mm in diameter on day of hCG administration. In the present study, we aim to further evaluate whether the double trigger improves the number of oocytes retrieved and the ratio between the number of oocytes retrieved per number of follicles > 14 mm in diameter on day of hCG administration.

Methods

All consecutive patients with poor oocytes yield, despite normal response to COH, due to low (<50%) number of oocytes retrieved per number of follicles > 14 mm in diameter on day of hCG administration, who were treated in our IVF unit during one year period were evaluated. Of whom, only those who received in the subsequent IVF cycle, a double trigger (GnRH-agonist and hCG) for final follicular maturation were included. The study was approved by the Institutional Research Ethics Board of our center.

All patients underwent the multi-dose GnRH-antagonist COH protocol during both IVF cycles. In both cycles, ovulation induction was performed by the administration of recombinant FSH, started at the 2nd or 3rd day of menses, using the same starting dose in each patient. Once the leading follicle had reached a size of 13 mm, or/and E2 levels exceeded 1200 pmol/L, co-treatment with the GnRH antagonist 0.25 mg/day, was initiated and the recombinant FSH was substituted by human menopausal gonadotropins. Gonadotropins doses were further adjusted according to serum estradiol levels and vaginal ultrasound measurements of follicular diameter, obtained every two or three days. Final follicular maturation was triggered by, either:

(1) In the first IVF cycles: recombinant hCG (Choriogonadotropin alfa, ovitrelle 250 mcg, Serono), 36 hours prior to OPU, or; (2) In subsequent cycles: the co-administration of GnRH-agonist (Triptorelin acetate, decapeptyl 0.2 mg, Ferring Pharmaceuticals, Israel) and recombinant hCG (250 mcg), 40 and 34 hours prior to oocyte retrieval, respectively.

Routine IVF or intracytoplasmic sperm injection (ICSI) was then performed, as appropriate. Transvaginal ET was performed 48 to 72 hours after OPU in both cycles. All patients received luteal support with progesterone.

Data on patient age and infertility-treatment-related variables were collected from the files. Ovarian stimulation characteristics, number of follicles >10 mm and >14 mm in diameter on day of hCG administration, number of oocytes retrieved, embryo quality and number of embryos transferred were assessed and compared between the study (double trigger) cycle and the previous (hCG-only trigger) control cycle.

Embryos classification was based on the individual embryo scoring parameters according to pre-established definitions [8]. While a top quality embryo (TQE) was defined as seven or more blastomeres on day 3, equally-sized blastomeres and <20% fragmentation, poor quality embryos consist of all the rest. Clinical pregnancy was defined as visualization of a gestational sac and fetal cardiac activity on transvaginal ultrasound.

Statistical analysis was performed with Student’s paired t-test and chi square, as appropriate. Results are presented as means ± standard deviations; p value < 0.05 was considered significant.

Results

Eight consecutive patients were evaluated. Mean age and body mass index during the study cycle were 38.0 ± 4.8 years and 27.7 + 5.4 kg/m2, respectively. The clinical characteristics of the IVF cycles in the two study cycles are shown in Table 1.

Table 1. Comparison between IVF cycles with hCG versus double trigger (GnRH-ag + hCG)

In the present study, while using the same COH protocols which differ only in the methods of triggering final follicular maturation, as expected, no differences were observed between the groups in the length of stimulation, the number of gonadotropin ampoules administered, peak estradiol and progesterone levels and numbers of follicles >10 mm and >14 mm in diameter on day of hCG administration. However, patients who received the double trigger (study group) had a significantly higher number of oocytes retrieved (7.0 ± 4.6 vs. 2.3 ± 2.5, p < 0.02), number of 2PN (6.0 ± 4.6 vs. 1.7 ± 1.2, p < 0.002), number of embryos transferred (2.2 ± 0.7 vs. 0.85 ± 0.9, p < 0.002) and significantly higher proportions of the number of oocytes retrieved to the number of follicles >10 mm (80.3% ±31.1% vs. 18.5% ± 16.6%, p < 0.001) and >14 mm in diameter (118.0% ± 71.2% vs. 23.7% ± 21.5%, p < 0.01) on day of hCG administration, with a tendency toward a higher number of TQE (3.7 ± 0.8 vs. 0.4 ± 0.5, p = 0.06) respectively, as compared to the hCG-only trigger cycles.

Five pregnancies were recorded in the study group and none in the hCG-only trigger group (Table 1). Of which, 3 are ongoing, one resulted in a blighted ovum and one was biochemical pregnancy.

Discussion

In the present preliminary cohort historical study, the co-administration of GnRH agonist and hCG for final oocyte maturation- 40 and 34 hours prior to OPU, respectively, to patients with poor oocytes yield due to low (<50%) number of oocytes retrieved per number of follicles > 14 mm in diameter on day of hCG administration, resulted in significantly higher numbers of oocytes’ retrieved and embryos transferred and a significantly higher proportion of the number of oocytes’ retrieved to number of preovulatory follicles. Of notice, the observed improved in oocyte yield was despite a non-significant decrease in the number of follicles of >14 mm and >10 mm on day of hCG administration.

Five biochemical (positive hCG) pregnancies were recorded in the study group (double trigger) and none in the hCG-only trigger group. Of which, 3 (37.5%) are ongoing and one resulted in a blighted ovum. However, it should be emphasized that the increased pregnancy rate in the study group (double trigger) is biased due to the study design which offered this protocol to patients who had failed a previous IVF attempt.

As part of a standard/conventional COH regimen, final oocyte maturation and resumption of meiosis are usually triggered by one bolus of hCG (5000–10,000 units), that is administered as close as possible to the time of ovulation (i.e. 36 hours before oocyte recovery) [2]. In 1990, Gonen et al. [9] have demonstrated that ovulation may be also triggered by GnRH agonist, causing the release of both endogenous LH and FSH, while in 2008, Shapiro et al. [10] have established the concept of ‘Dual trigger’, combining both hCG and GnRH-agonists, aiming to trigger ovulation with the questionable ability to prevent severe ovarian hyperstimulation syndrome [11,12].

Recently, Beck-Fruchter et al. [5] have described a case of recurrent empty follicle syndrome, successfully treated by ovulation trigger with GnRH agonist 40 hours and hCG added 34 hours prior to OPU. They assumed that by prolonging the time between ovulation triggering and OPU and the GnRH agonist trigger with the consequent simultaneous induction of an FSH surge, the “double trigger” could overcome any existing impairments in granulosa cell function, oocyte meiotic maturation or cumulus expansion, resulting in successful aspiration of mature oocytes, pregnancy and delivery.

In the present preliminary report, we further extended the aforementioned indications to the “double trigger” and offered it to patients with poor oocytes yield due to low (<50%) number of oocytes retrieved per number of follicles > 14 mm in diameter on day of hCG administration, despite an apparently normal follicular development and E2 levels during COH. While number of follicles of >14 mm and >10 mm on day of hCG administration wwere non-significantly decrease, we could demonstrate a significant increase in oocytes yield, a trend toward a higher number of TQE, with a reasonable clinical pregnancy rate. These observations are in agreement with Lin et al. [13], who compared the IVF outcome of normal responders, undergoing triggering of final oocyte maturation with either hCG and GnRH-agonist, both administered 35-36 hours prior to OPU, or hCG-only. The double trigger group demonstrated statistically significantly higher implantation, clinical pregnancy and live-birth rates as compared with the hCG trigger group.

Conclusions

“Double trigger” is suggested as a valuable new tool in the armamentarium for treating patients with low/poor oocytes yield, despite an apparently normal follicular development and E2 levels and in the presence of optimal hCG levels on the day of OPU. Further large prospective studies are needed to elucidate the aforementioned recommendation in this and other situations, such as patients with high proportion of immature oocytes or poor responder patients, prior to its routine implementation.

Abbreviations

COH: Controlled ovarian hyperstimulation; EFS: Empty follicle syndrome; hCG: Human chorionic gonadotropin; IVF-ET: In vitro fertilization-embryo transfer; OPU: Ovum pick-up; TQE: Top quality embryo.

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IVF #4 – Precycle CD3 – The 411

baby - ivf 4

Yesterday, I had my first precycling baseline appointment and bloodwork.  The transvaginal ultrasound shows that I have six follicles on my right ovary and three on the left. My blood work is all normal. I am now scheduled for my hysteroscopy with biopsy on January 9th at Lenox Hill Hospital, which will be my cycle day 20. I am continuing with weekly acupuncture as well.

Last night, Dr. Kiltz returned my call regarding the next steps of my protocol.  I spoke to Dr. Grossman earlier yesterday morning and he said we would defer to Dr. Kiltz’s protocol.  Dr. Kiltz had to look over my chart and figure out what he wanted to tweak for this protocol.  He stated he wanted to shake things up a bit.   Today, I got my precycle instructions for IVF#4.  I will be taking my normal supplements and prenatal vitamins until January 7th.  Starting on the 7th, I am to start taking Estrace tablets twice daily for seven days. Then I am to call with my next period to do a day three monitoring/ baseline appointment and start stims.  I will not be taking Estrace for three weeks and Endometrin the last week and starting Lupron like I did before.

I did discuss with Dr. Kiltz my desire to do a double trigger this next cycle, which is proven to mature eggs.  The hcg trigger shot is taken 36 hours prior to retrieval as normal.  The next morning, I will go in for blood work to test the hcg level and then that night, I will either do a lupron trigger of over 20 units or another hcg trigger.

I will be doing Saizen, 300 Gonal F, 300 Menopur, 5 Lupron (I assume) along with Synthroid and prenatals during stims.  After egg retrieval, I will add neupogen, lovenox, prednisone (20mg) and weekly intralipid infusions. I will be doing a two or three day transfer of all embryos this time instead of waiting until five day.

Merry Christmas to you all !

Amber Alert Cancelled – Cycle Day 1 – The 411

baby - found

Well guess who showed up this morning?  Aunt Flo.  This heifer took her behind on a seven day vacation and went AWOL.  Nobody gave this heifer permission to be absent without leave !  She did not even warn anyone that she was taking off for parts unknown.  She came back all relaxed and red as a beet.  I did not appreciate having to put out a medical search party for her tail either !

After I had time to calm down from my anger towards her, I realized that she was gone for seven days…. SEVEN.  My favorite number because is symbolized completion in God.  I remembered that I promised myself I would let go of the reigns and just let God be the pilot and focus on what I DO have control over and be the best and do the best with that.

So today is CD1 (cycle day 1).  Tomorrow, I will give Stacy, at Dr. K’s office a call so she can call Lenox Hill Hospital and get me scheduled for the hysteroscopy with biopsy on CD 20.  CD 21 fall on a weekend, so day 20 it will be.

Shortly after the procedure, I should get my next period around the third weekend of January and start stimming, provided everything is okay at baseline.  I will continue doing weekly acupuncture, doing weekly castor oil packs to increase blood flow to the reproductive organs and detox, and will take maca root every other day while taking the Estrace to avoid the cysts that always develop as a result of all that estrogen.

At the rate we are going, I will be back at a Christmas birth again !

I am dreading Christmas Day and I keep kicking myself for arranging my IVF around trying to have a baby on Christmas.  Would have been great had she survived, but now I will always remember May 15th (three days after the anniversary of my father’s passing) as the day she stopped developing, June 2nd, as the day I had to have her surgically removed from my womb, and December 25th as the day I had planned a scheduled c-section, to bring my child(ren) into the world on the day that is most significant to me.

No one understands what this feels like.  I feel like a dagger is piercing my soul the closer we get to Christmas.  I try to keep busy with “Christmas -y” stuff to keep my mind off of what I have turned this day into.  It is not working.  I am starting to despise that day.  I am sure I will get beyond it at some point, but right now, I just want to sit in it.

Update – The 411

baby - new update

I went home for a few days to see my OB, Dr. Karamitsos, so that I can do the pre-op appointment for my hysteroscopy and biopsy and follow up with him about my missing period.  The first thing Dr. K did was do a pregnancy test, which of course was negative.  It appears that the hormones I have been shooting myself up with since March, off and on, have just thrown my cycle out of wack a bit.

We have opted (along with my RE, Dr. Grossman at CNY) to just let my body do its thing and wait for my period to start on its own.  They could force it on by doing the hysteroscopy, but they feel that just waiting and letting my body work out its own kinks is best.  Dr. Grossman feels that forcing my period to come and rushing into a cycle is not what is best and if we do and the cycle fails, then we will be wondering if that was the cause.

I have waited this long to be a mom, so waiting out a little ole period is not that long.  Once my period starts, Dr. K will schedule me for the procedure on day 21 of the cycle.

After my doctors appointment, my mom and I went over to her favorite NYC restaurant, Pio Pio (a Peruvian restaurant) and met my awesome make up artist, Celebrity MUA, Bruce Hawkins, and had lunch.  Bruce will be seen having in depth discussions with me about the ins and outs of IVF in my reality series.

My mom and I went to see Motown the Musical last night and then grabbed food for her at Shake Shack.

This morning, I got up early and went to my dental appointment.  I was supposed to have oral surgery to have an extraction done, but the doctor wants to do a round of antibiotics first to heal an infection in the gum above the tooth and then do a cleaning the 1st week of January prior to doing the extraction.  I was relieved that I get to eat for Christmas and New Years. LOL.   I had already planned to wolf down protein shakes for the next several weeks.

I have been weight training for the past two weeks with my awesome trainer.  I go weight train in the morning at 5:30 am and then I go back to the gym in the evenings at 5pm to do an hour of cardio.  I am very worn out, but I am sticking to it with full gusto.

My Period Got Lost Along the Way This Month – The 411

baby - no freak out

I am trying to stay calm !  My monthly menstrual cycle should have started this past weekend, or at the latest on Monday, which was 31 days. Today is Tuesday and still a no show.  I have absolutely NO “period” symptoms.  No cramps….No excessive urination… no irritability (well no more than usual), no tenderness, nothing !  I see Dr. Karamitsos, my OB on Thursday morning, so if it still has not started, he can figure out why my body is tripping all of a sudden.  My period comes on like clockwork !

In other news, at my mom’s urging, I have embarked on my next publication and branding venture.  I am a wealth of knowledge regarding infertility and IVF.  I am penning a “how to” book on the ins and outs of fertility treatments and going to start doing public speaking and coaching.  I run into so many people who do not know what questions to ask, where to land medication discounts, how to determine which cryobanks are a good fit, how to select a fertility clinic, and so many other things one should know.  I have had patients ask me questions that they should have known the answers to LONG before ever starting fertility treatments.  I feel that I would be able to help a lot of women and also do something that I love.  I am also writing a screenplay for a short film about a woman’s search for the perfect donor.

I will keep you abreast of how things progress….

Update – The 411

baby - blog update

Where to begin….  I started working with my two trainers to get my body in tip top shape for my next cycle.  My trainer in Australia has me doing an hour and half of weight training in the am at 5 and then cardio in the evening for 30 mins to an hour at 5pm.   I have gone faithfully everyday with the exception of the evening cardio on Friday.  I was too sore from overworking it that morning with the clubs resident trainer who had me doing things not on my trainer’s list.  My trainer was a bit peeved because he doesn’t want me taxing my muscles like that.

I am doing 3 (35g) ready to drink protein shakes (Extreme Smoothies) daily and eating one meal at lunch which includes 28-35g of lean protein (normally chicken or fish) and a salad or cooked veggies.  I have sf jello if I get a sweet tooth.  I sometimes make a shake in my Vitamix with organic fruit.  I can tell a huge difference in my energy levels.  I am also doing weekly acupuncture along with my mom.

I am bit worried because today is CD 29 and I have not experienced a cramp, twinge, spotting, nothing….  Hopefully my period comes on tomorrow and I can schedule my baseline appointment for Wednesday.  I keep thinking in the back of my mind, what is going on?  Is it possible that my last cycle took and that bleeding last month with all that clotting was not a real period?  I have not had any bloodwork done since that negative beta.   It is probably just the acupuncture doing it’s job. I just want this period to start already so I can start my 3 weeks of Estrace, one week of progesterone inserts and Lupron and get ready for IVF#4, which I am declaring WILL work !

Currently, I am taking Inositol, Co Q 10, B6, Folic Acid, Vitamins C & D, Prenatal Plus Iron, and baby asprin.  I am doing my weekly castor oil packs as well.

On the mom front, my mom will be 1/2 way through chemo tomorrow.  It will be session 6. She is doing well.  Believe it or not, she is GAINING weight.  She eats ALL the time !  The cocktail of meds they have her on includes Dexymethesone and she is starving all the time.  Her blood cell counts are holding steady and her doctors are happy with her progress.

We are getting ready for Christmas.  We are putting together “blessing bags” which include toiletries, socks, hat, and gloves for the homeless and will give them out as well as breakfast sandwiches that we are having McDonald’s staff come in an hour early and make. A few actors from my last project are coming out to help us give out sandwiches.  I put a request on my Facebook page asking people to mail in blessing bag items or make a donation via Paypal and people have been really generous.  This has become and annual event we do on Christmas morning.  I love giving back and seeing the smile on faces who normally only bear a look of sorrow and despair.

Ba Hum Bug – Christmas Is Coming ! – The 411

Christmas tree 2014

The picture above is my 2014 Christmas Tree.  My mom wanted to do all silver this year for the family Christmas celebration. The whole family is usually together either at my mom’s or we pick a place to travel to.  We wanted to go to London this year, but with my mom’s cancer treatment, we are staying at home and taking a trip to Mexico a few weeks after Christmas.

The family, sans my sister and fam who reside in NC, spent Thanksgiving together. My sister and the fam were missed, but my sister has a new job and she only had the day off.  My mom was queasy all day on Thanksgiving so she laid down most of the day but felt better by dinner time.

I am finding myself starting to get depressed about Christmas.  I do not know how to explain it… it has been six months since I had the D&C and lost my daughter.  To feel a life growing inside you and then to suddenly feel that life leave you, it is hard.  I feel like a part of me is missing.  I loved that baby and was looking forward to her making her beautiful appearance on Christmas Day via scheduled c-section.  I have had two additional IVFs since losing her and neither took.

I am spending the next month and half working on dropping twenty to twenty-five pounds.  I have gained the weight with all the stim meds and excessive eating in the days after each transfer due to prednisone.  I absolutely HATE my body right now.  I ordered 35g protein shakes that I love and am drinking a detox and immune tea that I got from Herb Shoppe in New York.  I also picked up fat burners today.  I am on a mission !

My dating life has been going good.  The eye surgeon and I finally went out on Tuesday night.  He is very cool. He is so darn gorgeous, intelligent and funny.  We had a great time.  He wants to get together again soon.  I have also gone out with an IT consultant twice.  He is really nice.  He, too, is much shorter than I am, but he is a cutie and seems to be very into me.  So far, those are the two that I am dating.  I signed up for another site and am getting the lay of the land so to speak.  I am figuring things out.  I also signed up for Coffee Meets Bagel and for Tinder.  I figure I should keep my eyes and options open so that Mr. Right can find me.

If I can just get past the heavy sadness I am feeling every time I think of Christmas.  I wish I could just hop on a plane and go to a remote island in Fiji and not have to think about Christmas.  2014 was supposed to be MY year !  I was supposed to have the BEST Christmas EVER by having my daughter.  Harper Jean was supposed to come into the world on my favorite holiday.  Now, I will spend another Christmas watching others with their children.  I will spend another Christmas without being with my own family.  Two years ago, I was supposed to be getting married. In retrospect, it is a blessing that that did not happen.  Can you spell DISASTER?

Anyway, I hope everyone else is finding peace and is able to celebrate Christmas and have an amazing day ~