Plan B: Literature Review (Part II)

Discussion

Results were consistent with other studies showing that preovulatory administration of LNG …suppresses ovulation in most but not all cases…We could not, other wise demonstrate significant alterations in P4 and E2 during the luteal phase when LNG was administered at the time of LH surge or the day after the occurrence of FR. These observations strongly suggest that effects of LNG on the hypothalamic-pituitary-ovarian axis depend on the stage of the menstrual cycle at which the progestin is administered.

We can summarize these results as follows.

  • Cycle day 10: 80% didn’t ovulate and 20% ovulated but had shortened luteal phase.
  • After LH surge: no observed effect.
  • 48 hours after LH surge: no observed effect.
  • 2-4 days before LH surge: short luteal phase.

For the cycles in Group A that indicated ovulation, all had shortened luteal phases, but the overall length of each cycle was not significantly different from the control cases. This means that the follicular, i.e., pre-ovulatory, phase was longer than average. Group D was formed because urinary LH was a flawed indicator of LH surge and its use resulted in LNG administration earlier than intended. Coupled with the results of Group A, it seems that if LNG is administered too early, ovulation is not prevented.

In the present study, ovulation occurred in all those women treated immediately before the LH preovulatory surge (Group D); however, in these participants, deficient P4 production with a significantly shorter luteal phase length were observed. Findings in Group A were consistent with an impaired folicular maturation leading to deficient E2 and P4 production during the follicular and luteal phase, respectively…These observations indicate that the preovulatory effects of LNG on the hypothalamic-pituitary-unit are mediated, at least partially, by the progestin’s direct action on the growth, development, and steroidogenic capacity of the ovary to produce adequate E2 concentrations in serum as the primary signal triggering the LH surge…

That is, LNG may act by interfering with follicle development, which leads to deficient estrogen and progesterone production, thereby modifying (shortening, delaying, etc.) the LH surge and shortening the luteal phase.

The finding of ovulatory cycles in three participants belonging to Group A is unexplained but variations in absorption and clearance, as well as differences in ovarian sensitivity after LNG administration, should be considered among the causes of method failure.

They don’t know why some of the Group A participants ovulated, but they offer a suggested route of future inquiry.

On the other hand, the occurrence of ovulation in study participants receiving LNG within 3 days before the onset of LH peak (Group D) may represent either a null-effect or an amplifying P4-like effect of LNG on the hypothalamic-pituitary unit. Under physiological conditions, a small but significant rise in P4 has been considered as the ultimate ovarian signal to trigger gonadotropin preovulatory surge…In addition, P4 administration during follicular phase results in increased amplitude and decreased frequency of LH pulses, which is consistent with the pattern observed during the luteal phase of the cycle… These changes may partially reflect alterations in hypothalamic gonadotropin-releasing hormone secretion that, without apparently affecting preovulatory surge of LH and FR, could be involved in deficient P4 production observed during the luteal phase.

I’m not sure how to interpret this analysis. If I understand correctly, ovulation in Group D participants could mean either that the drug simply had no measurable effect or it acted by modifying the secretion of hormones not studied here, resulting in deficient production of progesterone during the luteal phase. Anyone with greater medical knowledge is encouraged to comment and correct me.

These results suggest that postovulatory contraceptive efficacy of LNG may not involve alterations in the mechanisms associated with endometrial receptivity…

Therefore, it is possible to conclude that interference of LNG with the mechanisms involved in initiating the LH preovulatory surge depends on the stage of follicular development. Thus, anovulation results from disrupting both normal development and hormonal activity of a growing follicle. In addition, the finding that LNG administration at late follicular phase (group D) did not interfere with E2-mediated midcycle gonadotropin surge and ovulation but otherwise did alter P4 production by the corpus luteum requires further investigation, particularly in those at both the ovarian and hypothalamic-pituitary unit, including the interference with preovulatory signals for adequate development and hormonal function of the human corpus luteum.

Since no evidence was found for endometrial effects using LNG, researchers must look to other postovulatory effects if any are be found. One such effect would be luteal insufficiency, i.e., a dysfunctional corpus luteum. The crucial question, in regard to the LNG potentially acting as abortifacient, is whether such luteal insufficiency would result in failed implantation or there would be no embryo to implant (due to some other action of the drug).

Our results may offer a plausible explanation for the contraceptive effects of LNG given postcoitally prior to LH surge or the mechanism involving corpus luteum development. In addition, this study does not support an anti-implantation contraceptive effect of LNG in EC; however, additional targets, besides those described herein, should also be considered and further investigated for the contraceptive effects of LNG.

IOW, these researchers found no evidence to support the hypothesis that LNG acts abortifaciently. However, they studied surgically sterilized women who could not possibly conceive. Therefore, we must be cautious to not apply these results too broadly. Also, though the endometrium was shown to be unaffected by LNG, other postovulatory effects were demonstrated (resulting in shortened luteal phase), leaving open the possibility of anti-implantation effects.

In the next installment, I’ll cover papers that report no postfertilization effects in rats and monkeys given LNG.

References

  1. Durand M, del Carmen Cravioto M, Raymond EG, Duran-Sanchez O, De la Luz Cruz-Hinojosa M, Castell-Rodriguez A, Schiavon R, Larrea F. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception 2001;64(4):227-234.

Comments 8

  1. Stuff wrote:

    Does anyone know whether 45 participants is statistically appropriate to draw generalizations from their findings? I know there’s all kinds of ethical and logistical problems with obtaining more, but I seem to remember from way, way back in pharmacy school tests you could perform to give more credibility to your study by showing the group sizes were appropriate. 45 just seems kind of small to me. Otherwise the study seems well-done.

    Posted 23 Oct 2006 at 5:44 pm
  2. Jerry wrote:

    Fallopian tube dysfunction is another postfertilization effect that has been mentioned. Have you seen anything on that? (And did that recent JAMA review I sent you prove at all useful?)

    Stuff: for a fairly involved human study, 45 isn’t necessarily too bad…

    Posted 23 Oct 2006 at 10:14 pm
  3. Funky Dung wrote:

    I haven’t read anything more current than 2001 about fallopian tube dysfunction. The Croxatto, et al., paper I presented in Part I had this to say:

    Alterations in embryo transport through the fallopian tube or uterus following EC, are also difficult to explore. Delayed transport or retention in the tube cannot be excluded a priori, although no increased incidence of tubal pregnancy has hitherto been reported with the current methods. Accelerated transport through the tube appears unlikely since neither estradiol nor progesterone given in high doses right after ovulation have this effect in women [102].

    Posted 24 Oct 2006 at 9:06 am
  4. cjmr wrote:

    45 participants would be too small for a safety or efficacy study, but for a ‘method of operation’ study that is a reasonable number.

    Posted 26 Oct 2006 at 7:58 pm
  5. Lightwave wrote:

    Maybe someone with a statistical background can help me out here. I know that any number of test subjects can be statistically significant depending on the desired confidence level one wants in the results. If we had statistics on the number of EC users, would we not be able to calculate the “confidence interval” for 45 test subjects? Thus we would know the confidence with which we can say these results apply to the general population.

    Would it not be fair to say that any confidence in these results (> 0%) is better than having no data and hence no confidence? i.e. the conclusions from data presented here is far more likely to be accurate than conclusions based on conjecture and assumptions on the effects of EC?

    Posted 30 Oct 2006 at 9:47 am
  6. Mariana wrote:

    Based on that study, I would say Plan B does not affect the endometrial lining, but it does affect the length of the luteal phase due to progesterone insufficiency. 80% of those taking the pill before ovulation and before the LH surge failed to ovulate, those who took it after the LH surge or right after ovulation noticed no effect.

    Given the pregnancy “prevention” rate of Plan B is 89% (including people who had sex after ovulation), and this study showed a prevention of ovulation of 80%, I would NOT draw the conclusion that Plan B was primarily abortifacient. I would recommend any woman taking Plan B to monitor herself for ovulation and supplement with progesterone to prevent a short luteal phase. I would not recommend women taking Plan B on ovulation day or later, because it is either unnecessary, inneffective, or potentially abortifacient.

    To me, it seems that from the study that the primary mode of action of Plan B is to prevent ovulation, not to damage the endometrium (no evidence of this mode of action). It can shorten the luteal phase, but that seems to be due to a crash in hormones, and theoretically could be prevented through progesterone supplementation.

    Of course, the results of one small study are not conclusive in any way.

    Based on this document: http://www.nccbuscc.org/prolife/issues/abortion/ecfact.htm It would be useful to know exactly when Plan B acts as an abortifacient and when it acts simply as a contraceptive. If the abortifacient action of Plan B is simply to shorten the luteal phase, the combination of a transvaginal ultrasound and progesterone supplements would be a good theoretical protocol to follow to avoid the misuse of the drug in cases of sexual assault.

    -Mariana

    Posted 04 Nov 2006 at 8:35 pm
  7. Raluka wrote:

    Please tell me what happened to the women from group A who took Postinor in day 10 of their cycle and still ovulated. I read on your blog that they had normal cycle length, while the luteal fhase was much shorter. Are this data from a study, is it written tehre or is only something you assumed? Thank you.

    Posted 18 Nov 2008 at 4:07 am
  8. Kabubu wrote:

    Day one of my last period was 12/26. I was raped on 1/1 and took plan B on 1/4. Today, 1/11, day 17 of my cycle, I had my period. My cycle is usually about 29 days long, give or take a 2-3 days. I felt none of the warning signs that generally accompany my period. In reading this, I am inclined to think that plan B may be the cause for this unusually short cycle. I will continue to monitor myself for any abnormalities and relate this to my doctor if the need to do so arises.

    Posted 12 Jan 2010 at 12:19 am

Trackbacks & Pingbacks 2

  1. From luminousmiseries on 24 Oct 2006 at 4:01 am

    brings us “Some thoughts on Suffering.” Recently Ales Rarus looked at a couple literature reviews about the methods of action of Plan B emergency contraception (levonorgestrel, LNG). This time it’s Plan B: Literature Review (Part II): On the the mechanisms of action of short-term levonorgestrel administration in emergency contraception (Durand, et al., 2001) If the blog name The Kitchenmadonna doesn’t make you want to click on through then maybe the post title

  2. From Participatory Bible Study Blog » Blog Archive » Christian Carnival CXLV on 25 Oct 2006 at 2:36 pm

    […] In the field of medicine and ethics, from Ales Rarus, we have Plan B: Literature Review (Part II). This is the second post in a series. Last time I looked at a couple literature reviews about the methods of action of Plan B emergency contraception (levonorgestrel, LNG). This time I’m presenting On the the mechanisms of action of short-term levonorgestrel administration in emergency contraception (Durand, et al., 2001). […]

Post a Comment

Your email is never published nor shared. Required fields are marked *