What is the uterine lining and why does it matter?

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

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

An 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 toward the fetus.ⁱⁱⁱ

Doctors and researchers use characteristics of the endometrium — such as endometrial pattern, endometrial blood flow, expression of specific proteins (growth and immune factors), and endometrial thickness (EMT) — to help predict endometrial receptivity and IVF success.

In IVF embryo transfers, sometimes even good quality or euploid embryos (embryos that have tested negative for chromosomal abnormalities) may fail to implant. The causes of implantation failure are variable and complex, but one cause may be an unreceptive endometrium at the time of transfer.

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

Endometrial thickness (EMT) fluctuates throughout the menstrual cycle. It 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. It is thinnest (an average of 4.4 mm) right after the menstrual period and increases to an average thickness of about 10.4 mm before ovulation in natural cycles. (Note: These average EMT values vary greatly between individuals.)

For people undergoing fertility treatment, endometrial thickness 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.^iv Most of the research, however, focuses on the endometrial thickness for embryo transfer cycles and there is a less clear understanding of optimal endometrial thickness for natural conception or intrauterine insemination (IUI) cycles.

There is a lack of agreement in the research as to whether endometrial thickness affects IVF success, but EMT assessment remains part of standard monitoring during fertility treatment and IVF cycles, and it provides useful information regarding response to treatment.^v

Endometrial pattern

In addition to thickness, the structure of the endometrium, called the endometrial pattern, changes throughout a person's menstrual cycle. It most commonly appears as a distinct triple-layered tissue (triple-line or trilaminar pattern) right before ovulation.^vi This trilaminar appearance is another important marker of endometrial receptivity and is associated with higher pregnancy rates in frozen embryo transfer cycles.^vii However, it can be difficult to visualize the trilaminar pattern on ultrasound. The angle of the endometrium in relation to the ultrasound probe can influence its appearance.

Uterine 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 during fresh IVF cycles is less than 7 mm or less than 8 mm on the day of the trigger shot (an injection of human chorionic gonadotropin, or hCG, taken approximately 36 hours before egg retrieval).^viii,ix Data from a large cohort of over 40,000 transfers showed that only about 3 to 4 percent of embryo transfers occur when endometrial lining thickness is under 7 mm.^x

One older clinical study observed that clinical pregnancy and live birth rates were significantly lower in patients with EMT of 7 to 8 mm compared with patients with EMT of 9 to 14 mm; clinical pregnancy rates were 18 percent vs. 30 percent and live birth rates were 14 percent vs. 25 percent. Cycles with an EMT less than 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 greater than or equal to 10 mm maximized the 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 regard 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 to 14.5 mm on the day of embryo transfer had optimal implantation (46.4 to 51.3 percent), clinical pregnancy (62.6 to 67.8 percent), and live birth rates (50 to 55.8 percent); if the endometrium was too thin or thick, these 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 to 2015 (see Tables 1 and 2).^xv In fresh transfer cycles, the clinical pregnancy and live birth rates were highest when EMT was greater than or equal to 8 mm and decreased as the EMT became thinner (Table 1).^xvi It is worth noting that embryo transfers with an EMT between 5 and 5.9 mm still resulted in a live birth rate of 18.7 percent compared to 33.7 percent for EMT greater than or equal to 8 mm. For frozen embryo transfers (FETs), the clinical pregnancy rate and live birth rates were highest when EMT was greater than or equal to 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 less than 6 mm.^xvii

Similar results were found in a retrospective study that analyzed EMT in 96,000 embryo transfers.^xx The live birth rate following fresh embryo transfers increased significantly with increased EMT until the EMT reached 10 to 12 mm, while the same effect was seen at 7 to 10 mm in patients undergoing frozen embryo transfer cycles. For patients undergoing both fresh and frozen embryo transfers, an endometrial thickness of less than 6 mm was associated with lower live birth rates.^xxi

Despite the trends noted above, there remains conflicting evidence for EMT affecting IVF outcomes. For example, a 2021 study found that EMT was not predictive of live birth rates in fresh or frozen transfers, suggesting that there may be too much emphasis placed on minimum thickness “cut-off” values for transfers.^xxii Similarly, a study by Ata et al (2023) on 959 euploid embryo transfer cycles found no correlation between endometrial thickness and live birth rates in either medicated or natural frozen embryo transfer cycles. Although this study was smaller in size, the conclusions are interesting given that only euploid embryos (embryos that tested negative for chromosomal abnormalities) were included, which, in theory, isolated the role of the endometrium in maintaining a healthy pregnancy.

Causes of thin endometrial lining

The causes of a thin lining vary between patients. Some patients even appear to naturally have a thinner lining, with no specific cause for it. For those with a naturally thin lining, an EMT measurement below 7 mm may be considered “normal” for that particular patient.

Here are some potential causes of a thin endometrium:^xxiii

• History of uterine surgeries (such as dilation and curettage (D&C))
• ‍Asherman’s syndrome (scarring within the uterine cavity)
• 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
• Certain ovulation induction drugs, such as Clomid

A thin endometrium is more common in older individuals, likely due to decreased vascularity and/or their hormone levels. In natural cycles, an incidence of 5 percent has been reported in females under 40 compared with 25 percent in females over 40.^xxiv In contrast, in cycles using assisted reproductive technology, a thin endometrium is detected in only 2.4 percent of patients and is generally associated with lower implantation rate and pregnancy rate.^xxv,xxvi

In the large Canadian cohort described above (Liu et al 2018),^xxvii it was observed that the chance of achieving an endometrial thickness greater than or equal to 8 mm decreased with age. (There was a 90 percent chance in females under 35 vs. 84 percent in females over 40.)

It is also worth noting that reduced pregnancy and live birth rates in patients with a thin endometrium may be at least partly due to their age (since success rates decline with age), as opposed to the thin endometrium itself.

Can the uterine lining be too thick?

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

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

Therefore, it is unclear whether an endometrium that develops to a thickness above the typical range seen for embryo transfer will have an impact on IVF success.

Endometrial hyperplasia

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

How to thicken the uterine lining naturally?

While there is a great deal of interest in ways to thicken the endometrial lining naturally or even with certain foods, very few of these strategies have been proven to work. 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 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. More studies are needed before treatments can be routinely recommended to patients.

Acupuncture

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 significantly thickened the endometrium.^xxx However, when acupuncture was used as a sole treatment, the effect in thickening the endometrium was not statistically significant.^xxxi

Vitamin E and L-arginine

Vitamin E and L-arginine were assessed in a small study by Takasaki et al (2010) in 61 patients with a thin uterine lining (less than 8 mm). Vitamin E improved endometrial thickness to over 8 mm in 13 out of 25 patients (52 percent). L-arginine improved endometrial thickness to over 8 mm in 6 out of 9 patients (67 percent).^xxxii The results of this study, however, are limited.

Platelet-rich plasma

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 that promote cell growth and proliferation.^xxxiii

One randomized controlled trial investigating 72 patients with a history of cancelled frozen embryo transfers due to a thin endometrium (less than 7 mm) observed an increase in EMT to about 7.21 mm after two PRP treatments in the same cycle.^xxxiv A second randomized controlled trial of 83 patients showed similar improvements to EMT following PRP treatment.^xxxv

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.^xxxvi

Foods and beverages

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

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. These treatments have a mechanism of action that could theoretically increase EMT; whether or not this mechanism translates to improved pregnancy outcomes has not been adequately assessed.

Adjuvant therapy (that is, a treatment or drug given in addition to a primary treatment to maximize its effectiveness) is commonly used in fertility treatment 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.

Aspirin

A 2019 review of published studies using aspirin to improve EMT did not observe any significant improvement in EMT or pregnancy rates for patients with EMT below 8 mm.^{xxxvii,xxxviii}

Viagra^®

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

Granulocyte colony-stimulating factor

Granulocyte colony-stimulating factor (G-CSF) 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. However, there is a lack of consistent evidence demonstrating an improvement in pregnancy or live birth rates.^xli One small randomized controlled trial of 141 participants did not observe any significant difference in EMT following G-CSF treatment.^xlii However, only six of these patients had an EMT below 7 mm, so it is unclear if G-CSF may stimulate thickening in patients with a thin endometrium.

Estrogen

There are different methods, dosages, and durations for administering estrogen (estradiol) to thicken the endometrium, including oral, vaginal, and transdermal (such as skin patches). There is a lack of evidence to determine which of these methods is best, but the oral route is most common. Each route has specific benefits:^xliii

• Oral is easiest to administer
• Transdermal administration produces the most stable release of estradiol
• Vaginal administration results in the highest blood serum and endometrial levels

If one method does not stimulate adequate endometrial growth, the patient can try one of the other two methods. One older study that compared vaginal to oral administration of estrogen observed an increase in EMT with extended vaginal administration in females with EMT less than 7 mm after taking oral estrogen.^xliv

Gonadotropin-releasing hormone agonists

Gonadotropin-releasing hormone (GnRH) agonists, such as triptorelin (brand name Decapeptyl^®), are another suggested treatment for a thin endometrium.^xlv 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 (less than 7 mm) who received injections of triptorelin (Decapeptyl^®, 0.1 mg) on egg 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 endometrial thickness (8.92 mm vs. 7.12 mm).^xlvi

What other factors contribute to endometrial receptivity?

Endometrial lining thickness is only one facet of endometrial receptivity when it comes to IVF embryo 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 level are believed to also be essential for embryo implantation. Impaired secretions can affect the structural and functional maturation of the endometrium.^xlvii 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).

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, canceling IVF treatment cycles is not always justified based solely on a thin endometrium.^xlix,l

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

Over the years, several treatments have been suggested to improve a patient’s EMT:

• Hormonal therapy (such as estrogen or GnRH-agonist)
• Infusion of growth and immune factors into the uterus

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 a patient’s fertility treatment cycles continue to fail, they may consider surrogacy (using a gestational carrier).^lii

Conclusion

Fertility doctors will likely monitor endometrial lining thickness during IVF cycles. However, other factors can be just as, if not more, important to the success of fertility treatment.

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 a thin endometrium, it is only one piece of a much larger puzzle.