Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
My wife recently went through an antagonist protocol (IVF#1) where she was on BCP for 3 weeks and then one day after stopping BCPs, they started her on (150cc Menopur and 150 cc Follistim). She ended up being a slow responder as her CD3 Estradiol was 22. After Day 3 they upped her Follistim to 225 cc. Her CD5 estradiol was 100 and it started to accelerate normally from there (topping off at 2300 at ER). However, her follicles grew slower than expected though consistently and they triggered when her estradiol dropped slightly on CD14 from 2500 to 2390 and her estradiol stayed the same after trigger. On the day before trigger her largest follicle was 17mm with about nine others in the 12-15mm range and some smaller ones. She ended up with 15 mature eggs, 9 fertilized, 8 to Day 3 and 2 good blasts to Day 5. So while the cycle ended up being decent with 2 blasts, I am concerned that this wasn’t the right protocol for her due to her very slow start but ultimate responsiveness to stimulation. I’ve heard this protocol sometimes also includes Lupron to “wake up” the LH receptors after BCP. Also, they started her on the stims the day after stopping BCP – it was my understanding you’re supposed to wait three days after stopping BCPs to begin stimulation?
Any general advice on protocol adjustments for round 2? For reference, her Day 3 AMH is 3.6, estradiol 6, and LSH 10.7 and she is 34 with AFC 12. Thanks!
In my opinion, the BCP should be overlapped with an agonist (e.g Lupron) in the last 3 days and then Lupron continued until the period starts at which point, depending on the protocol used the agonist should be reduced in dosage or supplanted by an antagonist until the day of the hCG “trigger”.
Dr Sher –
Thank you in advance for your response… We are undergoing FET in Feb – I have elevated NK cells. I was consoidering IVIG and can absolutely not afford it. I know the other much less option is Intralipid. Since the last posts on your blog is there any new information about Intralipid vs Ivig. This will be our 4th transfer and we are just trying to do as much research as possible – our clinic is pushing us the IVIG way but we just cannot afford multiple IVIG infusions during the process… again, thanks.
Both IVIG and IL are in my opinion equally effective in countering NKa. However, IL is far less expensive and unlike IVIG, its use is far less likely to cause side effects and complications.
There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL). Although there are many factors that contribute to such implantation dysfunction, in the final analysis it is activated, “functional” uterine natural killer cells (NKa) in association with cytotoxic-T cells (CTL), which, through the production of cytotoxic cytokines (see below), damage the “root system” (trophoblast) of the embryo, causing the pregnancy either to be immediately rejected or so compromising placentation that early pregnancy loss occurs. Both immunoglobulin-G (IVIG) and intralipid (IL) therapy given in combination with corticosteroids (e.g. dexamethasone, prednisone, and prednisolone) are used to effectively reduce/down-regulate activated NK cells.
NK cells reach the uterus from the woman’s bone marrow, early in the menstrual cycle, as so called “parental” or “progenitor” cells. There, these early NK cells proliferate under the effect of estrogen. Only upon being exposed to progesterone do they begin to propagate “functional” NK cells that release cytokines and promote implantation. The concentration of functional NK cells in the endometrium is maximal about 7 days after exposure to natural(endogenous), or synthetic (exogenous) progesterone ….i.e. corresponding to the time the time when the embryo implants into the uterine lining (endometrium).
Functional uterine natural killer (NK) cells as well as T-helper cells are immune cells that frequent the uterine lining. They produce growth factors known as cytokines that regulate orderly implantation of the embryo and facilitate placentation (development of a functional placenta, the baby’s life line).There are two varieties of uterine cytokines: a) TH-2 (humoral) cytokines that promote permeation of the uterine wall by the embryo’s trophoblast (“root system and, b) TH-1 (cellular) cytokines that oppose trophoblastic proliferation and permeation of the uterine wall by culling interstitial trophoblastic cells. Orderly implantation and formation of a functional placenta (lifeline of the baby) requires that TH-1 and TH2 activity be in equilibrium
There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).
•Autoimmune IID. Here, there is often a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g. Hashimoto’s hypothyroidism) etc. Autoimmune IID also occurs in about one third of cases of endometriosis, regardless of severity.
•Alloimmune IID. Here uterine NK cell activation results from uterine exposure to an embryo derived through fertilization of an egg by a spermatozoon which shares certain genetic (HLA/DQ alpha)characteristics with that of the mother or embryo recipient.
In both autoimmune and alloimmune IID, the end point is an excessive NKa/CTL, TH-1 release that damages the embryos trophoblast, resulting in failed implantation or early pregnancy loss.
It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the degree of NK cell activation (cytotoxicity) that matters. In fact, there are certain conditions (such as with endometriosis) in which the NK cell blood concentration is normal or well below normal and NK cell activation is markedly increased.
There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or TH-1 and TH-2 cytokines have been used with some success. However, use of the K-562 target cell test remains the gold standard. With this test, NK cells are isolated from the woman’s blood using Flow Cytometry and are incubated in the presence of specific “target cells”. These are then incubated together. The percentage (%) of “target cells” killed through exposure to NKa/CTL-TH1 cytokines is then quantified.
Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably. I have for 20 + years been working with Reproductive Immunology Associates (RIA) in Van Nuys, CA and preferentially recommend them to my patients.
There exists a pervasive but blatant misconception on the part of many, that the addition of IL/IVIG can have an immediate down-regulatory effect on NK cell activity. This has established a demand that Reproductive Immunology Reference Laboratories report on NK cell activity before and following exposure to IVIG and/or IL. However, the fact is that activated “functional” NK cells (NKa) cannot be deactivated in the laboratory. Effective down-regulation of activated NK cells can only be adequately accomplished if their activated “progenitor/parental” NK cells are first down-regulated. Thereupon once these down-regulated “precursor” NK cells are exposed to progesterone, they will begin spawning normal and functional NK cells, which takes about 10-14 days. It follows that to assess for a therapeutic response to IVIG/IL therapy would require that the patient first be treated (10-14 days prior to embryo transfer) and thereupon, about 2 weeks later, be retested. While at 1st glance this might seem to be a reasonable approach, in reality it would be of little clinical benefit because even if blood were to be drawn 10 -14 days after IL/IVIG treatment it would require an additional 10 days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.
Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells”. For this to happen, the IL/IVIG would have to down-regulate progenitor (parent) NK cell” activity. Thus, it should be infused several days prior to ovulation or progesterone administration so that the down-regulated “progenitor/precursor” NK cells” can propagate a sufficient number of normally regulated “functional NK cell” to be present at the implantation site 7 days later.
It is very regrettable that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.
Geoff Sher
800-780-7437
Hi Dr Sher, how much break do you normally recommend in between IVF cycles? Does your hormones/natural body cycle return to normal at the next period or does it normally take longer?
At least 1 full month off IVF treatment.
Geoff Sher
Hi Dr. Sher. I wrote you a question yesterday as well. Thank you for your excellent answer. You have confirmed my suspicions that my hormones/egg reserve are different than a younger woman and so my ivf should be different as well. My LH and testosterone are clearly higher so I am worried about using a protocol that will further increase those. I grow a few hairs in my chin. How I hate them. I pull them out. I did not have them in my twenties. I think it is a strong sign that my male hormones are higher than optimal. Would it help older women to try to block the male hormones with some sort of blocker? I had one male hormone test. The doctor said it was “normal”. I do not know. But having chin hair does not seem particularly normal to me. Sure it is normal for older women. So is osteoporosis, breaking hips after a fall, and so on. Heart attacks and strokes are “normal” in a lot of older people. So that means it should be accepted that nothing needs to be done about it?
Some Italian opera singer got pregnant naturally at the age of 55!! 55 unbelievable. She was on hormone replacement therapy. Maybe that is a coincidence but I never assume anything is a coincidence. A lot of scientific advancement comes from curious people taking note of patterns, exceptions to the rule and coincidence. As an opera singer, she may have had very careful hormone monitoring by a true specialist to make sure she did not lose her ability to sing soprano, sort of like how boys used to be castrated so they could stay tenors. It really made me wonder if I or my eggs might benefit from something that would help my body mimic a younger woman’s hormones.
By the way, thank you for doing these question/answer. It is very generous of you. We plan to call Julie D tomorrow.
Thank you for your response! I look forward to consulting with you!
Geoff Sher
I am currently 5 weeks 4 days pregnant and my doctor told me to stop my progesterone. Isn’t this way too soon???
I usually stop progesterone at 10 weeks but I advise you to follow your RE’s directive or discuss with him/her.
Geoff Sher.