Monday, July 7, 2008

New Information on the Effect of OCs on Endometrial Thickness [Serge]

I've appreciated the discussion between Lydia McGrew and Jason Dulle in the comments here regarding the effect of the follicular phase hormonal changes on endometrial thickness and potential for embryo implantation. There is an article in the latest issue of Contraception which may shed some light on these issues. I describe the study and comment in the end.

The study was done to compare two different regimens of OCs (24/4 cycle or a 21/7 cycle). They first took hormonal and ultrasound data from women not taking OCs (which are labeled "pre-treatment or cycle 1" on the graphs). They then took all of the women who ovulated and began one of the two treatment regimens (cycle 2). During the third cycle of treatment, they substituted a placebo for the first three pills in the cycle (attempting to simulate missed pills.) Lastly, they tested the women during their following cycle to see if any changes persisted. During cycle two, where the pills were taken correctly, one out of 100 women ovulated, but it was noted that she took antibiotics for scarlet fever during the study period. 4 additional women ovulated during cycle three, so the vast majority of women looked at had no luteal phase of their cycle.

Here is the data for the amount of E2 (estrogen) for the 3 groups:

As you can see, the E2 was significantly suppressed during all of cycle two. I was surprised that the E2 levels rose so quickly after 3 missed pills in cycle 3. Clearly, missing OCs greatly increases the chances of ovulation.

Here is the effect of the OCs on endometrial thickness:

First, the baseline max. endometrial thickness was at least 5mm for all women in this study. This differs from the data offered by Jason which claimed that the thickness of the endometrium was 1.1mm throughout the cycle for women on OCs. I can't claim that know which data is correct, but it seems clear they both can't be.

There was a slight increase in endometrial thickness for cycle three, where they missed the first three pills. Unfortunately, they were using mean values for the group, so the effect of those who ovulated were mixed in with the majority that did not. In other words, it is impossible to see if the luteal function of those who ovulated had significant impact on the endometrial lining. This would have been nice to see. Maybe I'll E-mail the authors and see whether they still have the information.

Lastly, the endometrial thickness rebounded to almost baseline very quickly after the pills were stopped. The post-treatment cycle was very close to the pre-treatment one - and the difference can be attributed to the fact that not all of the women ovulated in the post-treatment cycle.

Bottom Line: we still don't know for sure. This study only looked at one particular combination OC. It seems the max. endometrial lining for those on OCs is greater than 5mm and bounces back to its baseline level the following month after OCs are stopped. I believe this is indirect evidence against a post-fertilization effect, but I can't be definitive.


  1. This is timely! A lot of good info comes out of this study.

    It tells us that the endometrium is able to bounce back (roughly) to its regular thickness after a woman is off the pill, and begins to ovulate (at least for women who have not been on the pill that long).

    I think it also tells us that the endometrium is thick enough in women on the pill to be receptive to an embryo. The question is whether the 5mm measurements noted in this study are accurate, or the 1mm measurements noted in the other study are accurate. The former study used ultrasound imaging, while the latter used MRI. Which is more accurate?


  2. A few things strike me as strange--and I really just don't know what to make of them--about the chart for endometrial thicknesses. One thing is, how can the mean values for endometrial thicknesses in the post-pill cycle be _the same_ for the early and later parts of the cycle? I mean, that doesn't seem to make sense. You start out low and get thicker. Surely even the mean values should be different. Similarly, the means for the pre-treatment cycle seem only a little different. This seems odd.

    I don't know if the wider divergence from the mean on the non-pill cycles is relevant here at all, but it is pretty noticeable in the graph.

    Third, I notice that in the second part of the period in cycle 2, the thickness does show a somewhat thicker mean for the second part than for the first. I wonder to what this is to be attributed? A small amount of thickening over the period of the follicular stage, due to some follicle activity, though not enough for ovulation?

    Anyway, those graphs are interesting.

    Do let us know if you get any info. on the specific values for the ovulatory women in cycles 2 and 3.

  3. Lydia,

    The thickness values were "maximum endometrial thickness". They were not mean values as the thickness changed throughout the cycle - but mean values from the 100 women in the study. Sorry if I did not make that clear. The paper only reported on the maximum thickness.


    In general, MRIs are more accurate. However, US is more frequently used, and this difference cannot account for the 5 time difference in the two values. Something seems amiss with one of them.

    There could be other reasons. The combination pill could be different which could give different values. The number of women in the studies were different - this study had 100. I may try to find other studies to confirm this one. Thanks again for your interest and approach.

    BTW - I know I haven't addressed ectopic pregnancies. I may get to that eventually!

  4. Serge,

    I also wonder if the amount of time the women were on the Pill for has anything to do with it. If I recall, most of the women in the other study were on the pill for several years. My impression from this study was that none of these women had been on the pill prior to this study.


  5. Jason,

    The study stated that about 25% of the women were on oral contraception before the study began. They had to use an alternative method during the course of the study.

  6. DeCook, et. al., discuss the ectopic pregnancy issue explicitly and assert that they cannot find a single study that actually confirms a higher ectopic pregnancy rate with women on OC's than on no pill. They did find evidence of a higher rate with another method--I believe it was the mini-pill.

  7. I notice--using the scientific instruments of an image blow-up and a piece of paper as a straight-edge on my screen--that the thickest maximum endometrium in cycle 3 (where they deliberately missed the pills at the beginning) is almost at the level of the "bottom" women/woman of the group for cycle one and above the level of the "bottom" maximum thickness for the post-pill cycle. If we may conjecture that this thickest lining among the women in cycle 3 represents the ovulatory women (which might not be the case, but seems plausible as far as it goes) then it would seem that the ovulatory women in cycle 3 came up within the range of normal maximum endometrial thickness for a non-pill cycle. I would guess, eyeballing it, that it's something like 8 mm.

    Does this seem correct? If I'm misreading the chart, please do correct me here.

  8. Lydia,

    You may very well be right. It is assuming a bit, and we have to remember that only four women in cycle three ovulated, but your assumptions seems reasonable. The authors did not give the raw data - just the graphs for the endometrial thickness.

    BTW Lydia - I do not know the fair-use laws in this area. Is it OK for me to send you a copy of this paper (in pdf format)if you are interested (and Jason too)?

  9. Well, I've done it before--sending people a single copy of something for educational purposes--and thought it was okay. My strongest evidence for this is that Wesley Smith, who's a lawyer, offered right on his blog to send anybody a PDF copy of an article on brain death that he had access to. I don't know how good of an argument that is. :-)

    I notice that their abstract has an e-mail icon by on of the authors' names, so it shd. be easy to _ask_ about the raw data.

    In the name of honesty, I shd. also point out that by my same argument in the previous comment, the single woman who ovulated because of the antibiotics in Cycle 2 does not appear to have gotten more endometrial thickness total than maybe 7 mm? In other words, if we assume that the top thickness represents whoever ovulated, that top thickness is lower in cycle 2 than in cycle 3. This makes me wonder if I'm doing something wrong, but it cd. also mean that, in fact, total thickness just is lower with breakthrough caused by drug interaction while one takes all the pills (as happened with her) than with missing pills early in the cycle, presumably due to less pre-ovulatory thickening.

    Do they say how they measured ovulation?

  10. Yes, please email it to me at Thanks!

  11. So what is the final conclusion on this matter? Do OC's or don't they cause a "hostile endometrium" not favorable to implantation?
    I am very interested in this topic.
    Thank you.


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