Tuesday, 27 August 2013

Thin uterine lining is another frustrating cause of IVF Failure

The fertility problem arises when the patient has a poor Endometrium or a thin uterine lining. This could lead to low estrogen levels, poor blood flow or damaged Endometrium; the frustrating complex and unusual problem of a thin uterine lining often seen in infertile patients. One of the most challenging problems to deal with is that of the patient with a poor endometrium or a thin uterine lining. Embryos need to implant in the endometrium, and an optimal endometrium is thick and Trilaminar, One of the most frustrating problems in IVF today is the patient with a persistently poor (thin) uterine lining.

Normally, the endometrium should grow and become thick more than 8 mm and Trilaminar as the follicles grow, so that it is receptive and ready to accept the embryos when they are transferred into the uterine cavity. However, sometimes this does not happen. We do know that the growth of the endometrium depends upon:
·         The estrogen level in the blood
·         Blood flow to the uterus
·         The health of the endometrial tissue itself

Endometrial lining is routinely measured using the vaginal ultrasound in IVF cycles and is expected to be of adequate thickness for embryo implantation. An endometrial thickness of 8 mm or greater is generally considered adequate thickness and less than 7 mm has been associated with lower pregnancy rates, with almost no pregnancies observed with a lining less than 5 mm.

Poor endometrial lining most commonly occurs in women with a history of unexplained recurrent IVF failures or early recurrent miscarriages and is usually attributable to the following factors:
·         Endometritis: Chronic infection of the endometrial cells.
·         Fibroids of the uterine wall (non-cancerous muscle tumors of the uterus).
·         In-Utero exposure to the synthetic hormone called diethylstilbestrol. (DES)
·         Women using Clomiphene citrate.
·         Scar tissue of the endometrium. (Intra-uterine adhesions or formerly known as Asherman’s syndrome).
·         Distal tubal blockage (hydrosalpinx) and leakage of toxic fluid back into the uterus.

When thin endometrial lining is observed during an IVF cycle, additional estrogen in the form of vaginal suppositories may improve the overall endometrial thickness and outcome. Some investigators have used baby aspirin to improve the outcome, but results have been quite variable and most likely there is no benefit. Acupuncture and other relaxation techniques may be helpful in some cases, but large scale studies are needed to demonstrate a significant improvement with these treatment modalities. In some cases, the endometrial lining never reaches the acceptable thickness.

Sildenafil (Viagra) is a commonly used drug for erection problems in the male and has been shown to increase the penile blood flow. Investigators have used Viagra to increase the blood flow to the uterus with the hope of delivering more estrogen hormone to the uterine lining. Viagra vaginal suppositories can be used to achieve this goal in IVF cycles, in which the endometrial lining is thin despite additional vaginal estrogen treatment. In most cases of thin lining, the underlining cause can be identified and treated without the need for additional intervention.

A problem with any of these will cause the uterine lining to remain poor. Thus, poor estrogen levels will cause the lining to remain thin. This is commonly seen in patients who have a poor ovarian response. It's easy to check this by testing the estradiol level in the blood. If this is low, this is easy to treat by giving estradiol vale rate.

As with any other tissue, the uterine lining needs an adequate blood supply to develop optimally. Uterine blood flow can be measured by doing a colour Doppler. While it was originally hoped that this would provide useful information, sadly we still do not know what to do with this data. Doctors have tried improving uterine perfusion by treating these patients with vasodilators but the results have been mixed.

Sometimes, it's the endometrial tissue itself which has been damaged. This is often seen in patients who have had endometrial tuberculosis in the past. Similarly, uterine surgery can also disrupt the uterine lining. We find this in women who have had a dilatation and curettage done after having had a missed abortion. Over-enthusiastic curettage can result in the removal of the basal layer of the uterine lining, called the basalis. Once this has been denuded, new endometrial tissue cannot grow and the lining remains persistently thin, resulting in a variant of Asherman syndrome which is very difficult to treat.  A normal endometrium requires adequate blood flow; and high estrogen levels. Thus, if the lining is thin there are 3 possibilities: the estrogen levels may be low; the blood flow is poor; or the endometrium is damaged. We need to systematically examine all these 3 possibilities, so that we can pinpoint what the problem is in the individual patient, and then try to correct it.

If the doctor finds the endometrium is poor during the IVF cycle , often the best option is not to transfer the embryos but to freeze all of them. The patient can then be treated with high doses of exogenous estrogens, to see if this causes the endometrium to become thick. If the endometrium grows well , it's then possible to transfer the frozen embryos after thawing them into an estrogen primed endometrium.

However if the lining remains thin in spite of high doses of estrogen, this means the problem is either one of poor blood supply ; or a damaged endometrium. Some doctors have used color Doppler ultrasound to measure uterine blood flow, but the results with this have been mixed. Others have tried using Vaginal Viagra to try to improve endometrial blood flow. Since there is no reliable method to assess uterine blood flow, the next step is to determine whether the endometrium has been damaged or not. There are two possible causes of end-organ damage when the endometrium is nonresponsive. One is that the endometrium has been anatomically distorted because of intrauterine adhesions ( a common cause for this in India is uterine tuberculosis. This condition is called Asherman syndrome; and this can be diagnosed either with a Hysterosalpingogram, which shows filling defects within the uterine cavity; or with hysteroscopy, during which procedure the scars can be surgically removed.
If a patient has an unexpectedly poor lining during an IVF cycle, it's often best to freeze all the embryos rather than transfer them in the fresh cycle. We can then work on improving the uterine lining before transferring the frozen embryos back into the uterus.

If patients have a history of a poor lining, we use the following protocol to see if their lining responds to an increased dose of estrogen. However, if the uterine lining remains persistently thin, we try doubling the dose of Lynoral and repeating the scan. If it still does not improve, this confirms this is an end-organ defect in the endometrial tissue. This can be very difficult to treat. For these patients, we do a hysteroscopy, to confirm there is no correctable anatomic problem (for example, adhesions) which we can remove. We can also do an endometrial biopsy on Day 2 or 3 of the IVF cycle. This deliberate endometrial injury is supposed to provoke increased uterine blood flow, and sometimes causes the lining to improve.

Treatment options for specific causes:
 In cases of endometritis (infection of the uterine lining), an endometrial biopsy with documentation of chronic inflammation or with bacterial cultures confirms the diagnosis, which necessitates antibiotic treatment. Multidrug treatment for at least 7-10 days is recommended to eradicate chronic inflammation of the uterine lining. A repeat endometrial biopsy is not necessary to document resolution of inflammation and patients can resume fertility treatment within one menstrual cycle.

DES exposure is relatively uncommon in reproductive age women because its use in pregnancy was banned in 1971 in the United States. Although uterine malformations due to DES or most other causes cannot be corrected surgically, surrogacy in such cases results in excellent reproductive outcome. If fibroids are present, they can be surgically removed and the uterus can be reconstructed to establish a healthy pregnancy.

Clomid treatment can result in thin endometrial lining because the drug acts as an anti-estrogen at the level of the uterus. In such cases, either additional estrogen is administered along with Clomid or a different type of fertility medication is used. Alternatives are Femara, Tamoxifen or injectible FSH medications. Femara and Tamoxifen are oral medications, but they are not commonly used to induce ovulation or for the purpose of superovulation currently. Although their safety has been established by medical studies, a drug company warning on the use of Femara and risks on the developing fetus has limited its use in women trying to conceive. Among the three options, injectible FSH preparations result in the highest pregnancy rates and successful ovulation can be accomplished 100% of the time.

Intra-uterine adhesions or scar tissue can result from prior uterine infections, pelvic inflammatory disease, multiple uterine procedures, and prior termination of pregnancy or postpartum curettage of the uterine cavity. Hysteroscopic diagnosis and treatment of adhesions results in high pregnancy rates in most cases. Mild adhesions are relatively easy to treat, but severe adhesions generally need multiple hysteroscopic procedures to restore a normal uterine cavity. If adhesions are so severe that correction is not possible, surrogacy becomes a viable alternative treatment option.

Distal blockage of fallopian tubes (hydrosalpinx) results in accumulation of toxic fluid inside the tube that can drain back into the uterine cavity. Such drainage of toxic fluid can result in the diminishment of embryo binding sites called integrins in the uterine lining and result in no implantation, thin endometrial lining or miscarriages. It is almost standard practice currently to remove such diseased tissue (removal of blocked tube(s) – salpingectomy) by laparoscopy. Once the drainage of toxic fluid is eliminated, it has been shown that integrins (embryo binding sites) are replenished and pregnancy rates significantly increased.

Pregnancy rates with surrogacy treatment are much higher than patients who are trying to become pregnant and suffer from uterine problems including a thin endometrial lining. Even though surrogacy is the last option and not desirable initially, in some cases it may be the only option. A detailed discussion and evaluation with an infertility specialist is highly recommended in cases of uterine problems, especially thin endometrial lining.

For patients whose lining remains refractory to all therapeutic intervention, surrogacy is the final treatment option which has a very high success rate.


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