Friday, June 13, 2008

Help understanding how we know the mechanisms for emergency contraception

For my bioethics course, I want to present information about how Plan B and similar drugs work, and I want to get into some detail about the actual evidence here. I don't want to simply state dogmatically that plan B is contraception, like my dear friend Bitch. I don't even want to make the dogmatic statement alongside a capsule description of the causal mechanism, like PZ. I want discuss the methods by which this mechanism was verified.

So far, I've been looking at this review article, which I got via this nice post at the Well-Timed Period. (I'm slightly stymied here because I don't have access to a research library for the next two months(1).) The review article leaves me with questions, though. I don't know if I have readers who will answer them, but I'm listing them here at least for my own sake.

The review article covers Mifepristone and levonorgestrel, and lists seven targets they might effect:
  • Sperm transport and function
  • follicular development,
  • ovulation,
  • fertilization,
  • embryo development and transport,
  • endometrial receptivity and implantation,
  • the effects of the corpus luteum.
It basically organizes its discussion around this list but, it lumps ovulation and fertilization under the different heading "Oocyte maturation and fertilization."(2) The most important sections are on follicular development--which is the confirmed mode of action--and endometrial receptivity and implantation, and corpus luteum--which are potential modes of action that might get called "abortion". For each of these possible modes of action, you need to consider the effects of various dosages of the two drugs being considered and the timing of those doses. There are a lot of possible cases here, and I'd really like to see a big chart with all the possible combinations. As it is, it seems a lot of cases aren't covered. I can't find the data for the effects of levonorgestrel on the corpus luteum.

Follicular development

The authors write: Administration of mifepristone during the pre-ovulatory phase of the menstrual cycle either disrupts follicular development or inhibits ovulation(4).T he evidence for this seems to be that low doses administered at this time :
  • don't effect the endometrium, as measured by implantation rates
  • does effect the LH surge, as measured by blood tests
  • does inhibit the growth of which seem to be measured directly.

Question 1: How do the measure follicle growth in humans? Ultrasound?

With Levonorgestrel, similar evidence is given, except this time they explicitly say that they use ultrasound to measure follicle development and don't talk about the effect on the endometrium in humans, but do assert that "treatment with levonorgestrel in the rat and monkey does not effect fertilization or implantation"

Ok, The evidence here looks good. Both the existence of the mechanism and the effect are confirmed directly.

Endometrial development and implantation

This is where I start to get confused.(5) In the pre-ovulatory treatment section they assert
  • A standard dose of Mifepristone has a slight effect on endometrium development.
  • A larger than standard dose has a stronger effect, and also puts something I can't identify out of synch.
  • Levonorgestrel has no effect on endometrial development.

Question 2: Are the effects of pre-ovulatory use of mifepristone on endometrial development part of the evidence used to assert that RU486 used as EC can cause abortion

Question 3: Are these effects strong enough to effect implantation if the ovulation inhibiting effect failed?

Question 4: How is endometrial development being measured here? Is it using implantation rates, as before?

In the post ovulatory treatment section they assert:
  • "Treatment with a single does of 200mg of mifepristone on day LH +2 has been shown to be an effective contraception method. Early luteal phase treatment causes changes in [a bunch of processes] at the expected time of implantation"

Q5: Isn't this the famed blocking of implantation? Does this not count because the dose is too large?
  • "when a single does of 10 mg mifepristone was administered on day LH +2, the observed effect on the endometrium was less pronounced than after treatment with 200 mg or repeated low doses."
  • "In Bonnet monkeys, treatment with onapistrone in low doses ranging from 2.5 to 10 mg every day did not inhibit ovulation and had only a minor effect on endometrial morphology, but it was shown to be highly effective in inhibiting endometrial receptivity and implantation"

Q6: Are these points used to argue that Plan B is abortion? Is the reply here that the effect in the first study was too low, and the animal model involves the wrong dose and timing?

In that section they also assert
  • Post-ovulatory use of levonorgestrel has no effect on the endometrium. This sites the same study as the pre-ovulatory use of levonorgestrel.
Actually, now that I've worked through that, the questions don't seem to be as pressing as I thought they would be. I deleted a lot of them after I wrote them because I figured it out.

(1) This is not entirely true. I am staying in the small village where I used to be employed so that my kids can spend time with their old friends. I could go to the research library of my old university, and they might even let me in, but I feel weird slinking around my old place of employment.

(2) I find this irritating. Also the second sentence of the whole article is "The use of emergency contraception is largely under-utilized worldwide." This is even more irritating. Perhaps you think this is an example of why humanities people should not look at scientific journal articles. But look, this is scientific *communication* people. You are supposed to be clear, even when talking to each other. Every grammatical mistake, every pair of lists that is not parallel, makes it a little harder to follow what you are talking about. Sheesh.

(3) In this section they consider evidence that mifepristone blocks ovulation. Shouldn't this be discussed in the next section, "oocyte maturation and fertilization" which is supposed to correspond to "ovulation" and "fertilization" on their previous list? See note (2).

(4) One irritating thing, rather than being broken down by mifepristone and levongestrel, like the previous sections, this one is divided into pre-ovulatory and post-ovulatory treatment. See note (2)

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