Physician-To-Physician Consult

Dear Colleagues

I would like your advice on a case regarding thin endometrium.

36 yo Go patient with premature ovarian failure diagnosed at age 18. Patient took OCP's from age 18 until a few months ago when I saw her for donor egg. Normal evaluation including saline infusion sonogram. She has never had uterine surgery.

Patient did fresh donor egg cycle. I used Estrace 2mg BID with Vivelle patch for 2 weeks. Her endo lining was only 4 mm so I increased Estrace 2 mg TID vaginally (in addition to the Patch). After now a total of 22 days of estrogen, her lining was 5 mm. We did the transfer – biochemical pregnancy.

She had lots of frozen embryos. Did EEP frozen embryo protocol with estrogen 2 mg PV TID and patch – endo lining reached 5 mm after 35 days. Did transfer and no pregnancy.

My thought is that the endo was made atrophic from being on the OCP for so many years. So, I put her on Estrace + patch for 4 months. Just checked her endometrium – still 5 mm.

Not sure what to do at this point. She has 8 frozen embryos. Anyone have experience with Neupogen (Granulocyte Colony Stimulating Factor)? Patient cannot do gestational carrier ($$).

Advice appreciated.

Medical Director & President, Boston IVF
Associate Clinical Professor OBGYN| Harvard Medical School

View Answers

Answer by Robert Fischer

Dear Michael

I will suggest to do a Hysteroskopy to exclude any Pathology of the uterine cavity ,or chronic inflamation of the Endometrium.
I was successful in similar situation to prepare the endometrium giving Vaginal micronised Estrogens(Estrifam) 6-8mg per day (3x2mg or 4x2mg).
I also heard a presentatation two weeks ago from Prof Papanikolau from Thessaloniki injecting small doses of hCG (150i.u.) over a period of 7-10 days achiving by that regim a significant increase of the endometrium thinkness.
Try to contact him on this matter I do not have his e-mail but his name is Evangelos Papanikolaou He is lecturing at the Aristotle University of Thessalonikiand scientific director of HRG Greece.

I wish you luck
Kind regards

Answer by Juan Antonio García

Hi Michael,

These are the challenging cases! I have had 2 patients who did not respond to synthetic estrogens (patches, vaginal tablets, oral tablets...) and who did respond to natural estrogens; I gave them 1 amp of Menopur daily and with her own estrogens both of them did nice endometrium and conceived. Of course, tried on few more patients that did not work...
Regarding Gleicher's protocol with G-CSF as published in F&S, I have done 2 cases and both unsuccessful. In fact, one of them was a patient from Kuwait who had more than 15 or 20 IVF cycles in her country (no kidding!) and endometrium never went beyond 4mm according to her doctors. With G-CSF grew to 6mm, but did not conceive and now she has intrauterine adhesions that never had before. Is it due to G-CSF??
Let´s us know how this case goes.
Best wishes,

Dr.Juan Antonio García Velasco
Profesor Titular Obstetricia y Ginecología

Answer by Antonio Pellicer

Hi Michael,

This is a nice chat. Every patient is different and what Bob and Juancho suggested may or may not work. What I firmly believe is that endometrial thickness IS NOT the issue. The issue is whether this endometrium has got enough progesterone receptors to decidualize and allow the embryo to implant. In the past, I performed a mock cycle and did an endometrial histology the day of theoretical embryo implantation (P+5 in artificial cycles), and look for secretory transformation. Today, I use the ERA test developed by Carlos Simón and his team. If the molecular analysis tells me that the endometrium is receptive, I have ethical reasons to proceed with embryo replacements. We published many years ago pregnancies in oocyte donation with thin 4 mm endometria. When we did regression analysis of the different variables affecting outcome in oocyte donation, endometrial thickness was not a relevant factor. Thus, the functionality of this thin endometrium must be tested, despite trying other medical alternatives to make the endometrium grow.

Best regards

Answer by Robert F Casper

Hi Michael,

This woman was on OCPs for 28 years and that is the reason her lining is thin (see our paper in the green journal last year). The lining will not thicken with estrogen alone by any route. We tried the G-CSF in many patients like this over the last year and I have to agree with Juan that it doesn't work. Several years ago we did endometrial scraping in the luteal phase before a subsequent FET and got a few pregnancies in this type of patient even though the lining did not get thicker. This would fit with Dr Fischer's and Dr Pellicer's ideas since you could use a pipelle in a mock cycle and do endometrial histology and dating or gene profile to see if the lining appears to be functional. We have also tried the intrauterine hCG infusions about 15 minutes prior to embryo transfer as presented by Dr Aboulghar's group in women with previous failed IVF and good embryos with some success but not so far in women with thin lining. That might also be an interesting idea. The dose is 500 IU in 40 microlitres. We haven't yet tried menopur with estrogen as Juan mentioned. That might also be interesting if LH or FSH receptors in the endometrium are active.

Best wishes,

Robert F Casper MD, FRCS(C)
Professor, Division of Reproductive Sciences,
University of Toronto
Senior Investigator, Samuel Lunenfeld Research Institute,
Mount Sinai Hospital,
Medical Director, Toronto Centre for Advanced Reproductive Technology (TCART), Toronto, ON,
Medical Director, Insception Cord Blood Bank, Mississauga, ON

Answer by Alan Copperman

Hi Michael

We have treated patients with similar presentations, with varying degrees of success. Our usual regimen is similar to those proposed below: hysteroscopy, prolonged estrogen priming, Estring for local effects, baby aspirin, vaginal phosphodiesterease inhibitors, pentoxifylline, acupuncture, etc., with admittedly little data to support any of our treatment strategies. I am also interested in some of the murine in vitro data suggesting that co-administration of estrogen and progesterone appears to dramatically expand the endometrial epithelial progenitor cell pool.


Answer by Brian Kaplan

Michael ,

Challenging. Appreciate all the input as I too struggle with cases exhibiting ,thin,non responsive endometria.Have attempted the various adjuvants in vogue with limited results .
Hysteroscopy and timed endometrial bx to ascertain secretory transformation as suggested by others would be important and too have seen pregnancies with thinner linings but most will have a trilaminar architecture.
Have utilized HCG transfusion prior to ET ,as per Egyptian data, in 30 cases - not in a properly designed study, but clinical impression did not show much benefit .
We have just started utilizing Neupogen in a randomized study but no experience as yet. The case from Spain of adhesion formation is therefore of significant concern and will report if similar experience .
I know this is really a rarity and anecdotal but have seen 2 patients in last month from India , with a history of pelvic TB , diagnosed on uterine curretings ,needing GS,due to non responsive endometria.Has the patient been traveling internationally and is she from US?
Last question I have is her weight?
Thanks and I truly appreciate being included on e mail as I need the advice too .

Brian K. Chicago .

Answer by Zeev Shoham

Based on personal experience, since there are not many cases published similar the one described, and based on the literature available, I would suggest doing mechanical irritation with a Pipelle-like tool using the following protocol:

Start with four days of estrogen as administered previously. After four days, perform gentle mechanical irritation with the Pipelle-type catheter. Continue with estrogen administration. Changes should be seen after a few days.

This protocol is drawn from hands-on experience with several cases. The last case presented two months ago. A young woman was given Clomid for ovulation induction treatment; her endometrium was thin, although her estrogen level was heightened. She was switched to hMG and even though her estrogen was high, her endometrium was 4 mm thick. The patient was subsequently treated with higher doses of hMG and when the leading follicle was 14 mm wide with estradiol serum concentration of 2015 pmol/l, the thickness of the endometrium was 5 mm. During that time, she was offered and greed to underwent the Pipelle-type procedure and within two days, while the follicle continued growing, her endometrium grew to 8 mm and the patient conceived in that cycle.

The ability of the endometrium to thicken very quickly is documented in studies in hypo-hypo women.

Given the type of result described in the case above, I recommend performing the Pipelle-type irritation procedure in all unresolved cases of thin endometrium.

If you try this method, please let us know how it worked.

Zeev Shoham M.D.
Director of the Reproductive Medicine Unit
Kaplan Medical Center
Rehovot, Israel

Answer by Minas Mastrominas

Dear friend Michael
Hope you are flying in good health and happiness! Thin lining is very controvertial as you know better than me. I spoke with the Greek chap Papanikolaou Dr Fischer mentioned. He uses 150IU hCG daily from day 8th of the estrogen priming onwards till the day of progesterone supplementation. He claims cHG acts on LH endometrial gland receptors. There is no evidence thought and his paper was rejected from RBMonline.
I have seen pregnancies with 5 mm. I usually prefer to do Blast with poorer endometria. I also avoid prolonged estrogen priming (>14-16 days). I have noticed that thin but 3-line endometria lose that appearance with time.
I take this advantage to raise a question for our panel. I often see in young hyper-responding patients (>12 oocytes) especially PCO, endometrial waterish-serous sticky collection at the late follicular stimulation stage.
I aspirated the fluid on the collection day. Laboratory Analysis did not give me sound info about it, but whenever i saw it the pregnancy outcome was dismal. Now I freeze and transfer in natural cycle.
Any comments will be most appreciated!!
best regards to you and to all our distinguished panel colleagues

Minas Mastrominas MD
Embryogenesis IVF center

Answer by Milton Leong

Dear Michael

Long time ago, and probably still now, one of the British way of treating amenorrhea was by D+C - and it works!

It was explained as similar to turning or furrowing the soil to facilitate growth, a farm managent method from way back in the middle ages.

I have used this to success quite a few times. Nowadays when I have patients with repeated (persistent? better word) I do a hysteroscopy to rule out any pathology. The endometrium will usually appear thin and pale, of course, but often it also had patches of erythematous areas, which I think is from non-specific inflammation (endometriosis?). I then would do a D+C, and the thinner the endometrium the \"stronger\" the curretage. Afterwards I place an IUCD, like if I would have resected adhesions. Then I follow the mid-cycle endometrium thickness and blood flow. Often after 2-3 cycles the endometrial thickness and sub-endometrial blood flow increases. The IUCD is removed, and then the patient will go through estradiol preparation for FET. The endometrium will improve, and for further improvement of blood flow , vitamin E helps.

This is one of the \"unscientific\' without double blinded RCT treatments, and I am not ashamed to put it up here.

It works, and in the passed couple years (I looked up before writing this) I have treated 11 patients with endometrium less then 4mm, and only one has persistent endometrium less than 3mm. The cumulative pregnancy rate of the other 10 patients was 60 % with one miscarriage. The one who did not respond is now pursuing surrogacy.

I fully support finding out receptors too, but it is available to very few, and if I have access, I would like to study receptors before and after, and then correlate it with pregnancy or not. It would be interesting. (May be Carlo already had done these, and can tell us his results)





Answer by Leonid Genkin

I believe that the sonographic appearance of the endometrium is only the tip of the iceberg and the point is to discover what happens below the surface. The endometrium on US can be thin but normally structured, it can be sufficiently thick but lack the normal trilaminar view, or both, representing, probably, different conditions.

Like the majority of IVF practitioners I do not have the possibility to perform genomic studies of the endometrium or to check Estrogen or Progesterone receptors on everyday basis. In order to reveal whether abnormal US appearance correlate with
abnormal histologic structure I perform usually two diagnostic Pipelle biopsies in the same cycle, natural biphasic or Estrogen- progesterone sequential mock cycle under controlled conditions, which means measurement of E2 , Progesterone serum levels and Us on the day of biopsy. I do diagnostic hysteroscopy also usually in the same cycle. In the course of hysteroscopy abnormal signs, such as cervical or uterine adhesions are documented and treated ,if possible, others - atrophy, scarring, hyperemia, diffuse or patchy, suggestive of inflammation, adenomyosis are documented, endometrial and endocervical sampling performed.

In my experience, intrauterine adhesions were seen only in minority of cases. it was rare finding when multilayered endometrium was present on US. According to my impression, there is no strict parallelism between histology and sonographic data.
Very thin endometrium can still possess normal in -phase histology, or be out- of -phase, but still correlate to some extent with the dominant hormonal influence on the day of biopsy. In other cases the proliferative sample under E2 treatment can be followed by the absence of secretory changes under progesterone treatment, possible reflecting the P receptor problem.

In some patients endometrium remains \"inactive\" or \" non-cyclic\" both under estrogen and progesterone treatment, surely, disappointing finding. US Doppler is also useful, because it reveals non rarely scarce or absent vascularization of (sub) endometrium, possibly the result of impaired VEGF action.
Several remarks about the treatment.

The optimal variant of the FET cycle , I believe , is natural cycle , when E2 levels are physiologic .When E2 levels are low and the endometrium is thin there is no choice but to use E2 supplementation. I check always serum E2 levels during this treatment
in order not to reach high supraphysiologic levels so as not to cause the same problems with impaired endometrial receptivity as in the fresh IVF cycles. E2 serum levels 400 -1000 pmol/l should be sufficient to develop the endometrium. When with oral E2 use the serum E2 level is low, vaginal route- Estrofem 1mg/day is excellent option, but usually not 2mg/d ,which causes often very high E2 serum levels.
For years I tried vasoactive agents - Viagra, Nifedipin, Pentoxyphillin- and they were almost universally ineffective, not very surprising fact, taking into account scarce of absent endometrial blow flow in high proportion of patients with abnormal US endometruim picture.

They just have no substrate for the action of these preparations. Possible, some form of VEGF application could be useful.
Use of gonadotropins to stimulate endometrial growth as a rule was not effective. In fact, these patients usually have bad endometrium in the fresh gonadotropin - stimulated IVF cycles also.

With respect to possibility of impaired endometrial receptivity I tried long-acting GnRH analogs for two - three months before starting new ET cycle. It seems to be reasonably effective, resulting in sufficiently improved US endometrial view and several pregnancies.

In desperate cases I just ask the patient to stop temporally treatment attempts and to return after 3- 6 months or even longer \"calming\" period. Surprisingly ( or not? ) , substantial proportion of such patients returned with clearly improved endometrial image, and some of them were pregnant on there first US examination.
Obviously, Nature knows better how to treat thin endometrium.

Leonid Genkin, MD
IVF Unit
Assuta Hospital
Rishon -le- Zion



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