abortion, Bioethics, contraception, emergency contraception, fertility, medicine, morning after pill, Plan B

Progesterone, infertility, and early pregnancy

I spent the evening researching progesterone in early pregnancy and the FDA debate concerning the risk after ovulation and/or fertilization to any embryo that might be present when a woman or girl takes Plan B, which contains the progesterone, levonorgestrel.

More evidence that the Plan B formulation should not be a risk to the early pregnancy (after fertilization, before or after implantation) includes:

1. The statement by Dr. Linda C. Guidice, MD, PhD, then-Chair of the Advisory Committee on Reproductive Health Drugs (approximately page 202 of 314 of the document) to the joint meeting of FDA advisory committees concerning changing the status of Plan B to Over the counter:

DR. GIUDICE: Actually I have two comments. One is that a five-day window can be interpreted with the sperm being in the reproductive tract for 72 to 96 hours with a very late ovulation and with an effect of the levonorgestrel on a decreased release of the sperm in the cervical mucous or in the crypts of the fallopian tubes.
Secondly, for fertility therapy we commonly begin progesterone administration on post ovulatory day 2, and for infertility therapy with embryo transfer, we commonly begin supplemental progestin or progesterone one day before embryo transfer.
So I just want to make it very clear that administration of progesterone clinically early and periovulatory has no significant impact upon implantation rates.

 

2. Statement in the review of evidence (on p. 13)in the Government Accounting Office investigation into the circumstances surrounding the refusal to change the status, with footnotes:

ECPs have not been shown to cause a postfertilization event—a change in the uterus that could interfere with implantation of a fertilized egg.29 Some researchers argue that an interference with the implantation of a fertilized egg is unlikely to happen because progestins, whether natural or synthetic, help to sustain pregnancy.30 In addition, there is no evidence that one burst of levonorgestrel without estrogen can prevent implantation. However, researchers have concluded that the possibility of a postfertilization event cannot be ruled out, noting that it would be unethical and logistically difficult to conduct the necessary research.31 ECPs, including Plan B, do not interfere with an established pregnancy.

29Implantation is the embedding of the fertilized egg in the uterus six or seven days after fertilization. See A.L. Muller and others, “Postcoital Treatment with Levonorgestrel Does Not Disrupt Postfertilization Events in the Rat,” Contraception, vol. 67 (2003): 415-419.
30Horacio B. Croxatto, Maria E. Ortiz, and Andres L. Muller, “Mechanisms of Action of Emergency Contraception,” Steroids, vol. 68 (2003):1095-1098.
31It has not been possible to identify groups of women who had taken ECPs after fertilization so as to assess their effect on the establishment of a pregnancy. Therefore, there is no direct evidence, either for or against, the hypothesis that ECPs prevent pregnancy by affecting postfertilization events. See Croxatto, Ortiz, and Muller, “Mechanisms of Action of Emergency Contraception,” 1096.

 

3. Progesterone levels in early pregnancy, with graphs showing increase in progesteron after ovulation

4. Use of Progesterone in therapy for treatment of infertility and recurrent early pregnancy loss

Edited for formatting 5/1/13 – BBN

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Discussion

10 thoughts on “Progesterone, infertility, and early pregnancy

  1. >I've been doing some research on progesterone. What you say appears to be true. Only one small thing, the morning after pill, contains progestin, not progesterone. I'm still looking around to gather fact on any differences between to the two. You might also want to do some research to investigate any possible differences between progestin and progesterone.http://www.amazing-hgh.com/progesterone-side-effects.htm" The problem is that the media with the help of the pharmeceutical companies have confused doctors and the general public into thinking that Progesterone and Progestins are the same thing – clearly they are not. "

    Posted by Anonymous | February 6, 2008, 5:08 pm
  2. >Progesterone and levonorgestrel are both types of progestins. The latter was developed by researchers to mimic the former. (Beware of sites that are pushing human growth hormone and selling "anti-aging" medicines and creams. Search Pub-med at the National Center for Biotechnology, which has peer-reviewed literature on-line back to the '80's, at least. Where there's a correction or retraction, there's often a note on the search page. That's how doctors and the general public avoid confusion.)

    Posted by LifeEthics.org | February 11, 2008, 3:38 pm
  3. >I've found a study on the website you've provided. I'm little confused, but it seems to be about the effects of levonorgestrel on artery blood flow, could this method be abortifacient?Here's the studyhttp://www.ncbi.nlm.nih.gov/pubmed/18191844?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumOh and what about the report here:http://www.polycarp.org/larimore_stanford.htmIs the evidence cited here conclusive?PS Finding credible sources on the internet sure is hard.

    Posted by Anonymous | February 15, 2008, 8:06 am
  4. >Since this appears still to be an active thread, here's a question: If there is credible evidence that Plan B itself–which can be given without reference to the possibility that ovulation has already occurred–is quite unlikely to cause implantation failure, does this not have quite a lot of relevance for the claim one often hears that ordinary, lower-dose birth control pills cause implantation failure? It seems to me that anything that is evidence against progesterone's causing this effect in the one case also is evidence in the other case.I can see perhaps some failure of full relevance in just this sense: Long-term use of ordinary BCP's apparently does thin out the endometrium. That's why, for example, women on the Pill tend to have lighter periods than women who aren't. It might be argued that while the short "burst" of progesterone in the Plan B pills is unlikely to prevent implantation, the longer-term use of combination oral contraceptives is more likely to because it causes a more thorough thinning of the endometrium by long-term interruption of the normal functioning of the ovaries. Hence, if fertilization did occur while on ordinary BC pills, implantation failure would be more likely than after use of Plan B. I'm not sure if this is a sound argument, though, and especially given the lower likelihood of fertilization with faithfully taken birth control pills from the beginning of the cycle, it may be largely irrelevant. But I'd be interested in your take.

    Posted by Lydia McGrew | February 22, 2008, 1:33 am
  5. >Where did you see that long term BCP use could thin the endometrium? After all progesterone has been called the "pregnancy hormone", because it helps the endometrium. Granted, what's seen in the pills is synthetic.

    Posted by Anonymous | March 10, 2008, 12:22 am
  6. >I've seen it in so many places I couldn't even count them all. The BCP manufacturers themselves say it. The book _How Not to Get Pregnant_ says it. Physicians who prescribe BCP's say it, and it is a standard underpinning of the standard of care by gynecologists to tell patients experiencing break-through bleeding during early BCP use to wait three months, after which the breakthrough bleeding will stop. The reason given for the stopping of breakthrough bleeding is that by that time the endometrium has thinned. This is also the rationale given for lighter bleeding during menstrual periods while on the pill. It is also the reason behind the fact that some physicians will tell women who have been on birth control pills to go off them for three months and use some barrier method prior to attempting pregnancy, because the physicians believe there could be an increased risk of post-implantation miscarriage as a result of thinned endometrium. It's the basis of innumerable pro-life claims that birth-control pills cause silent abortions through implantation failure, and even pro-lifers who claim that they do not cause implantation failure grant the thinning of the endometrium but argue that the prevention of ovulation and thickening of cervical mucus successfully prevent fertilization so that implantation failures are highly unlikely to occur.And so on and so forth. It's supposed to be one of those "everybody knows it" things, and I'm not actually questioning it but just wondering how this report of the working of Plan B interacts with it.

    Posted by Lydia McGrew | March 20, 2008, 12:25 am
  7. >Here's one way of looking at it: Progesterones taken in pill form can _sustain_ whatever endometrium is in place, at least if it isn't too thick (hence breakthrough bleeding). But during a normal, fertile cycle, the endometrium builds up quite a bit. Then it's shed at menstruation. During a period of three weeks on BCP's, the endometrium doesn't build up nearly as much, because the ovaries aren't working at their usual pitch and estrogen levels from the pills are much lower than those produced by the ovaries in the usual female cycle. So the endometrium doesn't build up as much in the first place. The progesterone-estrogen combination in the pill does sustain the endometrium that is there (once breakthrough bleeding has stopped), so that the period does not begin until the pills are stopped in the fourth week. But you end up with a thinner endometrium gradually over time through the lack of ordinary ovarian activity.

    Posted by Lydia McGrew | March 20, 2008, 12:32 am
  8. >Hmm…interesting…would be curious to hear what this blogger thinks. Although, the hormone that build of the endometrium is the hormone estrogen, if there isn't enough estrogen to build of the endometrium, then wouldn't that also mean that there isn't enough estrogen for ovulation? Just a thought.

    Posted by Anonymous | March 20, 2008, 5:48 am
  9. >Yes, it does usually mean that. That's why suppression of ovulation is the primary mechanism for birth control pills. We do know that sometimes breakthrough ovulation takes place, though, from the simple fact that women do become detectibly pregnant while on the pill. That is, even used perfectly, it has a failure rate for detectable pregnancy (that is, with implantation)–I believe this was calculated at 2or 3 percent per 100 woman-years or something like that.The remaining question, then, is how likely it is that breakthrough ovulation would take place, that implantation would occur, and (a separate question) that this would be attributable to the effects of the pills themselves rather than being something that would have happened anyway.My own guess is that this is _not_ likely. The zygote is pretty penetrative under normal circumstances, and the very fact that women do have both ovulation and implantation occur while on the pill seems to indicate a tendency for the body's "override" to be total–that is, for accidental ovulation to be correlated with a sufficient estrogen effect for implantation as well. On the other hand, we have in the nature of things almost no direct data, as implantation failures would be almost by definition not directly detectible. One study found ovarian _activity_ in something like 11 percent of women on the pill, but ovarian activity is not the same thing as full ovulation. Some people don't know this.And natural implantation failure probably takes place even in women who are not on the pill. And if some of those women had ovulated, they might not have conceived anyway, or the child might have implanted successfully.So the probability of implantation failure _caused_ by birth control pills is very difficult to calculate exactly.

    Posted by Lydia McGrew | March 21, 2008, 11:27 pm
  10. >"…that implantation would occur"Sorry, that should be "that implantation _failure_ would occur." I was writing quickly and just now noticed the problem upon re-reading.

    Posted by Lydia McGrew | March 22, 2008, 1:31 am

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