The Thin Endometrium

A thin endometrium is defined by ultrasound when the endometrial thickness is measured at its widest point in a longitudinal axis before ovulation in the late follicular phase of the cycle.  Most research defines a thin endometrium as being less than 7mm representing 2.4% of the fertility population, although some use 6mm or 8 mm as a cutoff.

Although data shows a positive correlation between endometrial thickness and clinical pregnancy rates, the thickness of the endometrium does not predict pregnancy for an individual and some women with a thin endometrium do conceive.  One large study suggested a negative correlation between endometrial thickness and miscarriage and ectopic pregnancy but this needs to be confirmed by future studies.

A thin endometrium is not a diagnosis in itself and the underlying pathology may differ between individuals and require different treatments. Therefore, after considering how thin is thin and when, we need to move to determine why the endometrium is thin and what are the best treatments.

A thin endometrium (generally defined as <7mm) is associated with poor implantation rates in assisted reproduction technologies (ART).  But what causes a thin endometrium and how does it limit implantation.  This short lecture will summarize the major contributors to a thin endometrium, which can be grouped into two main categories: physical damage and hormone (estrogen) disruption.  Physical damage to the basal layer of the endometrium can cause scar tissue and adhesions, as well as upsetting the balance of stem cells required for regeneration of the endometrium during the menstrual cycle.  Endometrial growth and development are predominantly regulated by relative levels of estrogen and progesterone, therefore any disruption to this balance will also cause dysregulation of endometrial growth.  It is still not fully clear how a thin endometrium affects implantation in women.  But it has been hypothesized that increased blood flow, resulting from a shorter distance to the radial and spiral arteries, increasing the oxygen content of the functional layer of the endometrium which is disadvantageous for the implanting embryo.  In addition, it could be speculated that thinning of the endometrium also alters the relative leucocyte populations (uterine natural killer cells, macrophages, T cell subsets) that are crucial for establishing maternal-fetal tolerance, preparing the endometrium for implantation, and in decidual remodeling during early pregnancy.  However, more research is required to fully understand the causes and pathogenesis of a thin endometrium.  This knowledge will aid in development of therapeutic options for women seeking to optimize their reproductive health.

There are several underlying causes for the thin endometrium, but intrauterine Adhesions (IUA) is a common reason for the condition. Medical management of IUA is of limited value. Surgical treatment seems to be the only effective treatment option. The traditional surgical techniques include the cold steel (scissors) or hot wire (diathermy). Two new surgical modalities, balloon therapy and invisible knife, will be introduced. These various methods will be compared to each other and the choice of the method in different situations will be discussed. A major challenge of surgery is the high rate of recurrence of IUA. Currently available methods to reduce recurrence will be reviewed. Strategies for primary prevention of IUA will also be recommended.

This presentation reviews the available evidence on the therapeutic management of thin endometrium in assisted reproductive technology using hormones.

An endometrium is usually defined as thin as it fails to grow beyond a certain thickness, usually 7mm. This has been shown to be associated with reduced likelihood of pregnancy following an embryo transfer. Its incidence is around 2.4%.

Endometrial growth during the proliferative phase is tightly linked to hormones and specifically estrogen. There are different forms of natural estrogen, yet estradiol plays the dominant role in endometrial growth. The evidence around the optimal dose of estradiol, the optimal route and the duration of administration are reviewed.

Other hormonal treatments including the use of tamoxifen, human chorionic gonadotrophin, midluteal GnRH agonist administration and growth hormone are also reviewed.

Endometrium is one of the number of factors involved in achieving optimal outcomes after infertility and assisted reproductive treatment. Optimal endometrial thickness (>7 – 8 mm) and appropriate endometrial receptivity is required for pregnancy and live birth outcomes in ovarian stimulation and IVF (fresh and frozen cycles) Thin endometrium is challenging occurrence in infertility management and assisted reproduction. Several treatment modalities have been suggested and used in patients with thin endometrium, to improve endometrial thickness and the subsequent endometrial receptivity.  I summarize the different medical strategies (hCG, Midluteal GnRH-agonist, Tamoxifen, G-CSF, Sildenafil, Pentoxifylline with Vitamin E, Nitroglycerin and L arginine) that have been investigated in patients with thin endometrium, so as to provide some solid evidence of therapies that may be beneficial and help us move away from empirism. Most current treatments are based on anecdotal cases and have not been validated so far. This is because most studies on these treatment strategies includes a very small sample size and most were non-randomised trials or cohort studies although worldwide many doctors and patients use them. Currently, there is minimal evidence to support any specific protocols or adjuvants to significantly improve pregnancy outcomes in patients with thin endometrium.

Among multiple available treatment options, vaginal sildenafil during the stimulation cycle may be a reasonable first line treatment option, whereas intrauterine G-CSF infusion before ovulation trigger could be a second line treatment option, provided large randomized studies evaluating outcomes, which includes best time point in a cycle (and at what dose) to administer these therapies. When offering these therapies, we must also look at its safety, effectiveness, and cost, before adopting them.

Platelet rich plasma (PRP) is an increasingly used biological material in many areas of regenerative medicine.  There is no consensus on the definition of PRP but there are increasing reports of intrauterine use of PRP as an add-on in women with a thin endometrium undertaking medically assisted reproduction.   The use of PRP in treatment of the thin endometrium is biologically plausible and supported by animal studies but there is little data on protocols of use, preparation of PRP and adverse outcomes in humans.  Whilst a number of cohort studies have reported improvements in surrogate outcomes there is no data on live birth outcome and obstetric outcomes such as low birth weight and placental abnormalities.  There is a single small randomised controlled trial investigating the use of PRP in women with a thin endometrium.  Whilst PRP is a promising innovation in treatment of the thin endometrium there is need for randomised trials with objective and standardised preparation of the PRP with the primary outcome of live birth.