What is the uterine lining and why does it matter?

The function of the uterine lining (endometrium) is to support embryo implantation, maintain pregnancy if implantation occurs, and menstruate (shed the lining) in the absence of pregnancy. The endometrium is a dynamic tissue that involves both the endocrine (hormonal) and immune systems and changes with estrogen and progesterone levels throughout the menstrual cycle.ⁱ  

Endometrial receptivity refers to the physiological quality of the endometrium that allows the embryo to properly attach and implant in the uterine wall. The window of implantation (WOI) is roughly a 4-day window that occurs about 7-10 days after ovulation (mid-luteal or mid-secretory phase of the menstrual cycle) in most natural cycles.ⁱⁱ

The embryo must attach to the uterine lining to remain viable and continue its development into a fetus. Embryo implantation also stimulates the endometrium to be remodeled into a structure known as the “decidua,” which allows molecular secretions and an increase of immune cells to create a nourishing environment to maintain pregnancy. The decidua also transforms the uterine immune system to prevent any immunological reaction towards the fetus.ⁱⁱⁱ

Characteristics of the endometrium, such as endometrial pattern, endometrial blood flow, expression of specific proteins (growth and immune factors), and endometrial thickness (EMT) assist in the prediction of endometrial receptivity and IVF success.  

In IVF embryo transfers, even good quality and/or genetically tested euploid embryos may fail to implant. The causes of implantation failure are variable and complex, but one reason may be an unreceptive endometrium at the time of transfer.

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How thick should the uterine lining be when trying to conceive?

Endometrial thickness is directly impacted by estrogen levels leading up to ovulation and reaches its maximum thickness at the onset of the luteinizing hormone (LH) surge (in natural cycles). Endometrial thickness fluctuates throughout the menstrual cycle. It is thinnest (average 4.4 mm) right after menstruation and increases to an average of about 10.4 mm before ovulation in natural cycles. These average EMT values vary greatly between patients.

EMT is measured by ultrasound, and a thickness that is less than 7 mm (the most common cut-off) has historically been considered “thin” and therefore may be less optimal to support embryo implantation in ART cycles.^iv There is a lack of consensus on the clinical significance of endometrial thickness for IVF outcomes, but EMT assessment remains part of the standard monitoring during fertility treatment and IVF cycles, and it provides useful information regarding response to treatment.^v It is unclear if EMT is a useful tool in IUI. There is a lack of consistent research evidence and consensus as to whether a thin endometrium is associated with low pregnancy rates for IUI patients.^vi

In addition to thickness, the structure of the endometrium, or endometrial pattern, changes throughout the menstrual cycle and it most commonly appears as a distinct triple-layered tissue (triple-line or trilaminar pattern) right before ovulation.^vii However, the angle of the endometrium in relation to the ultrasound probe can influence this appearance.

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Lining thickness for embryo transfer

As mentioned, the importance of endometrial thickness in IVF outcomes is debated, but EMT assessment is a standard part of monitoring during fertility treatment and many patients seek information about “ideal” thickness of the uterine lining.  

The cut-off value for classifying a thin endometrium differs between studies but a common threshold used is <7 mm or <8 mm on the trigger day of fresh IVF cycles (human chorionic gonadotropin (hCG) administration.^viii,ix Data from a large cohort of over 40,000 transfers showed that only about 3-4 percent of embryo transfers occur when endometrial lining thickness is below 7 mm.^x    

One clinical study by El-Toukhy et al (2008) observed that clinical pregnancy and live birth rates were significantly lower in patients with EMT of 7-8 mm compared with those with EMT of 9-14 mm; clinical pregnancy rates were 18 percent vs. 30 percent and live birth rates 14 percent vs. 25 percent. Cycles with an EMT <7 mm were often cancelled, and the pregnancy rate was only 7 percent.^xi A study by Gallos et al (2018) analyzed 25 767 IVF cycles and observed that an optimal EMT of ≥10 mm maximized live birth rate (33.1 percent) and minimized pregnancy losses (26.5 percent).^xii

In another large study, Shaodi et al (2020) investigated the impact of EMT on the day of embryo transfer with regards to the outcomes of 10 165 medicated frozen embryo transfers (FETs).^xiii They observed that cycles with an EMT within the range of 8.7-14.5 mm on the day of embryo transfer had optimal implantation (46.4-51.3 percent), clinical pregnancy (62.6-67.8 percent), and live birth rates (50-55.8 percent); if the endometrium was too thin or thick, the observed rates were reduced.^xiv

One large clinical study by Liu et al (2018) analyzed the impact of endometrial thickness on IVF outcomes of 40 000 Canadian embryo transfers from 2013-2015 (see Table 1, 2).^xv In fresh transfer cycles, the clinical pregnancy and live birth rates were highest when EMT was ≥8 mm and decreased as the EMT became thinner (Table 1).^xvi It is worth noting that embryo transfers with an EMT between 5-5.9mm still resulted in a live birth rate of 18.7 percent compared to 33.7 percent for EMT >=8mm. For frozen embryo transfers (FETs), the clinical pregnancy rate and live birth rates were highest when EMT was ≥7 mm and decreased as the EMT became thinner (Table 2). In both fresh and frozen embryo transfers, less than 1 percent of patients underwent an embryo transfer with an EMT <6 mm.^xvii

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Table 1. The endometrial lining thickness chart below shows the thickness of the endometrium during fresh embryo transfer and associated clinical pregnancy and live birth rate outcomes in a large clinical study. Adapted from Liu et al 2018.^xviii

Table 2.  Thickness of the endometrium during frozen embryo transfer (FET) and associated clinical pregnancy and live birth rates in a large clinical study. Includes cleavage stage and blastocyst transfers. Adapted from Liu et al 2018.^xix

Despite the trends noted above, there remains conflicting evidence for EMT and IVF outcomes. For example, a recent 2021 study found that EMT was not predictive of live birth rates in fresh or frozen ETs, suggesting that there may be too much emphasis placed on minimum thickness “cut-off” values for transfers.^xx

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Causes of thin endometrial lining

The causes for a thin lining are variable between patients, and some patients appear to naturally have a thinner lining, with no specific acquired cause for it. For those with a naturally thin lining, having EMT below 7mm may be considered “normal” for that particular patient.

Some potential causes of a thin endometrium include a history of uterine surgeries such as dilatation and curettage (D&C), Asherman’s syndrome, pelvic radiation, endometritis (infection/inflammation of the endometrium), uterine fibroids, premature ovarian insufficiency (ovaries that stop functioning normally before the age of 40), low estrogen levels, increased age, or certain ovarian stimulation drugs such as Clomid^®.^xxi

A thin endometrium is more common in older women. An incidence of 5 percent has been reported in women <40 years of age and 25 percent in women >40 years of age in natural cycles.^xxii A thin endometrium is seen more often in older females likely due to decreased vascularity and/or hormone levels. In ART cycles, a thin endometrium is detected in only 2.4 percent of patients and is generally associated with lower implantation rate and pregnancy rate^xxiii,xxiv In the large Canadian cohort described above (Liu et al 2018),^xxv it was observed that the chance of achieving an endometrial thickness ≥8 mm decreased with age (90 percent chance in women under 35yr vs 84 percent in women above 40yr). It is also worth noting that the reduced pregnancy and live birth rates in those with a thin endometrium may be at least in part due to age (since success rates decline with age), as opposed to EMT itself.    

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Can the uterine lining be too thick?  

While most studies examine the effect of a thin endometrium in IVF transfers, the evidence is conflicting on whether a uterine lining can be too thick in terms of IVF transfer.

Findings from the study by Shaodi et al (2020) showed that when the endometrium was above 15mm on the day of transfer, slightly lower live birth rates were observed.^xxvi In contrast, in a retrospective study of over 6 000 females undergoing fresh transfers, the live birth rates were highest among women with endometrial thickness above 17 mm.^xxvii  

As such, if the endometrium develops to a thickness above the typical range seen for embryo transfer, it is unclear as to whether this impacts IVF outcomes.  

An increased thickness of the endometrium in IVF cycles should not be confused with endometrial hyperplasia. While this condition involves excessive endometrial thickness, the endometrium is also irregular, and often the lining’s cells and endometrial glands can be abnormal.  Endometrial hyperplasia is most often examined when there is a potential risk of endometrial cancer and it should not be confused with an overly thick regular lining during fertility treatments.

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How to thicken the uterine lining naturally?

While there is a great deal of interest in ways to thicken the endometrial lining more naturally or even with certain foods, very few have been assessed in a clinical setting. In practice, treatments used to increase EMT are administered based on their theoretical mechanism of action rather than a proven effect. For patients with a thin EMT, often a result of age or endometrial injury, some commonly proposed treatments may not result in a clinically significant benefit. The studies described below assessed change in endometrial thickness in response to treatment for a limited number of patients and did not assess pregnancy outcomes. Studies assessing live birth outcomes, in adequate sample sizes, and unbiased populations are needed before treatments can be routinely recommended to patients.

Acupuncture to improve EMT has been assessed in various studies. A 2019 systematic review and meta-analysis of several studies found that acupuncture used in conjunction with medication showed a statistically significant thickening of the endometrium.^xxviii When acupuncture was used as a sole treatment, the effect in thickening the endometrium was not statistically significant.^xxix

Vitamin E and L-arginine were assessed in a small study by Takasaki et al (2010), in 61 patients with a thin uterine lining (<8mm). Vitamin E improved endometrial thickness to over 8mm in 13 out of (52 percent) 25 patients. L-arginine improved endometrial thickness to over 8mm in six out of 9 patients (67 percent).^xxx

Platelet-rich plasma (PRP) infusion/injection into the uterus before embryo transfer is a recent treatment option designed to potentially stimulate thickening of a thin endometrium and improve receptivity. PRP is a concentrated component of a patient’s own blood, with higher-than-normal levels of platelets. It contains proteins involved in immunity and various growth factors (promote cell growth and proliferation).^xxxi One randomized control trial investigating 72 patients with a history of cancelled FETs due to a thin endometrium (<7 mm) observed an increase in EMT to about 7.21 mm after two PRP treatments in the same cycle.^xxxii A second randomized control trial of 83 patients showed similar improvements to EMT following uterine PRP.^xxxiii However, these studies are small and have limitations. When looking at all published uterine PRP studies, the evidence is mixed (some show no effect on EMT, others show improvement) and researchers cite a need for larger, better-designed trials.^xxxiv

Other suggestions common to online support groups include consuming pomegranate juice, raspberry leaf tea, and Brazil nuts, among others. However, there is no published clinical evidence to support the use of these for improving EMT.  

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Which medications can help thicken the uterine lining?

If the uterine lining is too thin, several medical treatments, including hormone therapy, may be recommended to encourage endometrial changes. While these treatments have a mechanism of action that could theoretically increase the EMT, whether or not this translates to improved pregnancy outcomes has not yet been adequately assessed.

Adjuvant therapy (treatment or drug given in addition to the primary treatment to maximize its effectiveness) is commonly used in ART and sometimes for thin endometrium. Studies have compared the use of some common treatments, such as Aspirin^®, Viagra^®, granulocyte colony-stimulating factor (G-CSF), and estrogen.  

A 2019 review of published studies using Aspirin to improve EMT did not observe any significant improvement in EMT or pregnancy rates for those with EMT below 8mm.^xxxv,xxxvi

There is some evidence for use of 50-100 mg/day of sildenafil citrate (Viagra^®) intravaginally to improve EMT in patients undergoing FETs. One small, randomized control trial of 80 patients with a history of thin EMT (undergoing FETs) showed that the endometrial thickness was significantly higher in the sildenafil citrate group compared to the controls (not receiving sildenafil).^xxxvii Another small study also showed an improvement in EMT (11 out of 12 patients) with sildenafil citrate.^xxxviii

Granulocyte colony-stimulating factor is an immune factor that stimulates the development of neutrophils (white blood cells), and studies suggest that injecting G-CSF into the uterus may improve EMT but there is a lack of consistent evidence demonstrating an improvement in pregnancy or live birth rates.^xxxix One small randomized controlled trial of 141 participants did not observe any significant difference in EMT following G-CSF treatment.^xl However, only six of these patients had an EMT below 7mm, so it is unclear if G-CSF may stimulate thickening in patients with thin endometrium.

There are different methods and dosage/duration for administering estrogen (estradiol), including oral, vaginal, and transdermal administration. There is a lack of evidence to determine advantages for oral versus vaginal or transdermal administration, but the oral route is most common. Each route has specific benefits: oral is easiest to administer, the transdermal route produces the most stable release of estradiol, and the vaginal route results in the highest blood serum and endometrial levels.^xli If one route of administration does not stimulate adequate endometrial growth, a different route could be considered. One older study that compared vaginal to oral administration of estrogen observed an increase in EMT with extended vaginal administration.^xlii

Another suggested treatment for a thin endometrium is a gonadotropin-releasing hormone (GnRH) agonist, such as Decapeptyl^®;xliii GnRH is a hormone that normally stimulates physiological processes that regulate the menstrual cycle and ovulation. One clinical study observed that infertile patients with a thin endometrium (<7 mm) who received injections of triptorelin (Decapeptyl^®,0.1 mg) on oocyte retrieval day, embryo transfer day, and three days later had significantly higher implantation rates (21.4 percent vs. 7.3 percent), pregnancy rates (36 percent vs. 13.5 percent), and EMT (8.92 mm vs. 7.12 mm).^xliv

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What other factors contribute to endometrial receptivity?

Endometrial lining thickness is only one facet of endometrial receptivity when it comes to IVF transfer.  Endometrial receptivity requires synchronized and regulated functions by different cell types in the uterus and involves several immune factors, growth factors, and biologically active molecules secreted by endometrial cells.

The endometrium is also responsible for secreting uterine fluid into the uterine cavity. Uterine fluid is a complex solution of ions, steroid hormones (precursor proteins important for estrogen and progesterone production), carbohydrates, amino acids, proteins, and other factors, and its volume and pH are believed to also be essential for embryo implantation; impaired secretions can affect the structural and functional maturation of the endometrium.^xlv The chart below gives a closer look at some factors that may affect the endometrium and available methods that can be used to assess the endometrium (Table 3).  

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Table 3. Methods available to assess the endometrium. Adapted from Craciunas et al. 2019 ^xlvi

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What options exist if uterine lining thickness can't be improved?

Physicians and patients are often confronted with the difficult decision of whether to continue with embryo transfer in cycles with a poor EMT. Review studies suggest that although pregnancy prospects improve with a thicker EMT, cancelling IVF treatment cycles is not always justified based solely on a thin endometrium.^xlvii  

The cut-off value for a thin endometrium varies between clinical studies and although most studies use the cut-off of <7 mm, pregnancy has been observed after embryo transfer in patients with an EMT as low as 3.8 mm on the day of hCG administration (trigger day in ovarian stimulation cycles).^xlviii  

Over the years, several treatments have been suggested that include hormonal therapy (such as estrogen or GnRH-agonist) or other medical treatments (infusion of growth and immune factors into the uterus) to improve a patient’s EMT. However, most options achieve only minor changes in EMT and may or may not improve pregnancy outcomes. Treatment of a thin endometrium or poor endometrial receptivity remains a challenge, and if their ART cycles continue to fail, patients may consider surrogacy (using a gestational carrier).^xlix  

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Conclusion

While endometrial lining thickness will likely be assessed during IVF cycles, other factors can be just as, if not more, important.  

The overall goal during treatment is to ensure that the physiological state of the body is most capable of being receptive to an embryo. While it is easy to feel disheartened when an endometrial evaluation reveals something like endometrial thinness, this is only one piece of a much larger puzzle.

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