Endometrium thickness

For every single cycle, my final endometrium thickness has been 7 mm or below. For this last cycle it reached a maximum of 6.7 mm. I know this is bad, but how bad is it? I did some research for myself today, and wrote up my findings.

Endometrium Thickness
During the follicular stage of the cycle, estradiol released by the developing follicles to stimulate endometrial proliferation. In general, the greater the proliferation, the thicker the endometrium.

In both fresh and frozen IVF cycles, a thinner endometrium is associated with lower pregnancy rates. In one study of 1382 fresh IVF cycles, endometrial thickness of less than 10 mm on the day of transfer was significantly associated with lower pregnancy rates (Kovacs et al., 2003). One study of 768 FET cycles found that live birth rates were 1.9-fold lower in women with endometrial thickness of 7-8 mm compared to women with thickness of 9-14 mm, after adjusting for confounding variables. The lowest pregnancy rates were found in women with endometrial thickness less than 7 mm (El-Toukhy, et al., 2008). Biochemical pregnancies have been associated with a thinner endometrium (Dickey, et al., 1992).

Association or causation?
Of course these studies are not saying that a thin endometrium is causing implantation failure. It may be a proxy for another factor. However, in one study logistical regression found no association between endometrial thickness and embryo quality or age (Kovacs et al., 2003).

Multivariate analysis has concluded that endometrial development is one of the factors that play a significant role in IVF outcome. Other variables such as age, embryo quality, number of embryos transferred and stimulation protocol were also shown to have a significant impact on treatment outcome.

Does increasing endometrial thickness improve pregnancy outcome?
Numerous possible treatments for increasing endometrial thickness have been proposed. These include aspirin, tamoxifen, sildenafil, and estrogen.


Low-dose aspirin
Aspirin (acetylsalicylic acid) has anti-inflammatory, vasodilatory and platelet aggregation inhibition properties, and may promote uterine blood flow. Randomized clinical trials have produced conflicting results on the beneficial effects of aspirin in IVF.

One meta-analysis of 10 randomised clinical studies of fresh and frozen IVF cycles found that clinical pregnancies were 1.15-fold higher in low dose aspirin groups than placebo groups (Ruopp, et al, 2007). However, aspirin does not appear to improve endometrial thickness (Haapsamo, et al., 2009), and subsequent randomised placebo-controlled trials have failed to find a significant difference in pregnancy rates between aspirin-treated and non-aspirin treated groups (Dirckx, et al., 2009).

So if there is a positive effect of aspirin on the success of IVF cycles, it is very small, and not associated with changes in endometrial thickness.

Tamoxifen
I was only able to find a single study that examined tamoxifen and the endometrium. This study compared the use of supplemental Clomid or Tamoxifen in addition to injectable gonadotrophins in IUI cycles, and found that patients taking tamoxifen had increased endometrial thickness and improved ongoing pregnancy rates (Wang, et al., 2008). Tamoxifen is generally only used in IVF cycles in cancer patients.

Sildenafil
This magic blue pill has been found to improve blood flow by enhancing the release of nitric oxide and thus relaxing vascular smooth muscle. Does it also affect womens’ reproductive organs in a similar manner?

One randomised placebo-controlled study of 15 non-pregnant, nulliparous women found that sildenafil improved uterine volumetric flow during the luteal phase of their cycle (Hale, et al., 2010).

In a pilot study, 105 infertile women were recruited with prior IVF failures attributed to poor endometrial thickness

Estrogen
Estrogen supplementation during stimulation with Clomid during IUI cycles has been shown to improve endometrial development and to result in thicker endometria and improved morphology (Gerli et al., 2000; Elkind‐Hirsch et al., 2002).

Similarly, a placebo-controlled randomised trial of 81 women demonstrated that oral estrogen supplementation throughout a fresh IVF cycle was associated with increased pregnancy rates. The estrogren group had significantly thicker endometrial thickness and a 1.9-fold higher pregnancy rate (Jung and Roh, 1999). Supplementing progestrone with estrogen purely in the luteal phase has also been shown to increase pregnancy rates compared to progestrone-only supplementation during the luteal phase (Var, et al., 2010)

Conclusions
Supplemental sildenafil and estrogen may improve endometrial thickness and pregnancy rates in women with prior IVF failures due to thin endometriums. The evidence for estrogen is currently stronger than that for sildenafil.

Personal Implications
I am going to contact my clinic and ask them about the possibility of adding estrogen (and perhaps sildenafil) to my next fresh IVF cycle.

References

P. Kovacs, Sz. Matyas, K. Boda, and S.G. Kaali. The effect of endometrial thickness on IVF/ICSI outcome Hum. Reprod. (2003) 18(11): 2337-2341

Geoffrey Sher and Jeffrey D. Fisch. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF Hum. Reprod. (2000) 15(4): 806-809.

Geoffrey Sher and Jeffrey D. Fisch. Effect of vaginal sildenafil on the outcome of in vitrofertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertility and Sterility. Volume 78, Issue 5, November 2002, Pages 1073-1076.

Sarah A. Hale, Cresta W. Jones, George Osol, Adrienne Schonberg, Gary J. Badger, and Ira M. Bernstein. Sildenafil Increases Uterine Blood Flow in Nonpregnant Nulliparous Women. Reproductive Sciences April 2010 17:358-365

Marcus D. Ruopp, Tara C. Collins, Brian W. Whitcomb,and Enrique F. Schisterman. Evidence of Absence or Absence of Evidence? A Re-analysis of the Effects of Low-Dose Aspirin in IVF. Fertil Steril. 2008 July; 90(1): 71–76.

Mervi Haapsamo, Hannu Martikainen, and Juha Räsänen. Low-dose aspirin and uterine haemodynamics on the day of embryo transfer in women undergoing IVF/ICSI: a randomized, placebo-controlled, double-blind study. Hum. Reprod. (2009) 24(4): 861-866

K. Dirckx, P. Cabri, A. Merien, L. Galajdova, J. Gerris, M. Dhont, and P. De Sutter
Does low-dose aspirin improve pregnancy rate in IVF/ICSI? A randomized double-blind placebo controlled trialHum. Reprod. (2009) 24(4): 856-860

Tarek El-Toukhy, Arri Coomarasamy, Mohammed Khairy, Kamal Sunkara, Paul Seed, Yacoub Khalaf, Peter Braude, The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles, Fertility and Sterility, Volume 89, Issue 4, April 2008, Pages 832-839

Hyuk Jung and Hyoung Kyun Roh. The Effects of E2 Supplementation from the Early Proliferative Phase to the Late Secretory Phase of the Endometrium in hMG-Stimulated IVF-ET. JOURNAL OF ASSISTED REPRODUCTION AND GENETICS. Volume 17, Number 1, 28-33

Turgut Var, Esra Aysin Tonguc, Melike Doganay, Cavidan Gulerman, Tayfun Gungor, Leyla Mollamahmutoglu, A comparison of the effects of three different luteal phase support protocols on in vitro fertilization outcomes: a randomized clinical trial, Fertility and Sterility, In Press, Corrected Proof, Available online 2 August 2010