On the mechanisms of action of short-term levonorgestrel administration

On the mechanisms of action of short-term levonorgestrel administration in emergency contraception

Marta Durand, Ma. del Carmen Cravioto, Elizabeth G. Raymond, Ofelia Duran-Sanchez, Ma. De la Luz Cruz-Hinojosa, Andre´s Castell-Rodrıguez, Raffaela Schiavond, Fernando Larrea, Department of Reproductive Biology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubiran, Mexico City, Mexico Family Health International, Research Triangle Park, NC, USA Department of Cellular Biology, School of Medicine, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico Reproductive Health Service, Instituto Nacional de Pediatrı´a, Mexico City, Mexico

The effects of short-term administration of levonorgestrel (LNG) at different stages of the ovarian cycle on the pituitary-ovarian axis, corpus luteum function, and endometrium were investigated. Forty-five surgically sterilized women were studied during two menstrual cycles. In the second cycle, each women received two doses of 0.75 mg LNG taken 12 h apart on day 10 of the cycle (Group A), at the time of serum luteinizing hormone (LH) surge (Group B), 48 h after positive detection of urinary LH (Group C), or late follicular phase (Group D). In both cycles, transvaginal ultrasound and serum LH were performed from the detection of urinary LH until ovulation. Serum estradiol (E2) and progesterone (P4) were measured during the complete luteal phase. In addition, an endometrial biopsy was taken at day LH _ 9. Eighty percent of participants in Group A were anovulatory, the remaining (three participants) presented significant shortness of the luteal phase with notably lower luteal P4 serum concentrations. In Groups B and C, no significant differences on either cycle length or luteal P4 and E2 serum concentrations were observed between the untreated and treated cycles. Participants in Group D had normal cycle length but significantly lower luteal P4 serum concentrations. Endometrial histology was normal in all ovulatory-treated cycles. It is suggested that interference of LNG with the mechanisms initiating the LH preovulatory surge depends on the stage of follicle development. Thus, anovulation results from disrupting the normal development and/or the hormonal activity of the growing follicle only when LNG is given preovulatory. In addition, peri- and post-ovulatory administration of LNG did not impair corpus luteum function or endometrial morphology. © 2001 Elsevier Science Inc. All rights reserved.

Levonorgestrel (LNG) is a synthetic 13_-ethyl substituted 19-nor steroid [1,2] with potent progestational activity and is widely used in contraceptive formulations. LNG represents the active isomer of norgestrel and is administered orally or delivered either via an intrauterine device or from subdermal implants [3]. Alone or in combination with estrogenic compounds, LNG has also been used successfully for postcoital contraception [4]. In this regard, postcoital administration of steroids is a well recognized, effective means for preventing pregnancy, currently representing a widely accepted method of emergency contraception (EC). Although efficacy is generally not as high as with other contraceptive methods, EC significantly reduces the risk of an unwanted pregnancy. Indeed, when administered within 72 h of unprotected intercourse, LNG prevented about 85% of pregnancies compared with the expected number without treatment [5].

All emergency methods in use act before implantation through mechanisms probably involving interference with sperm penetration, transport and/or fertilization, follicular growth and corpus luteum development, and/or by a direct action on the endometrium [6 –9]. LNG could work by altering any of these mechanisms depending on the day of the cycle at which the contraceptive is given. There are few studies designed to look at the mechanisms of action of LNG as a postcoital contraceptive, in particular those considering the fact that women may require the method at different times during the menstrual cycle [10–14]. In this study, we have investigated in normal menstruating women the effects of LNG on the pituitary-ovarian axis, corpus luteum function, and endometrium when two doses of 0.75 mg are given orally 12 h apart, during the follicular (day 10), peri-ovulatory [luteinizing hormone (LH) surge] and postovulatory (48 h after urinary LH detection) phases of the cycle. This study was designed by taking into consideration the expected variability of the menstrual cycle among women and, therefore, the need to reassign the initially allocated participants into study groups by normalizing, within the cycle, the time of administration of LNG according to the onset of LH surge in serum. The rationale for the timed treatment schedule was also based on the probabilities of conception by cycle day as reported by Wilcox et al. [15].

The study was approved by the Human Ethical and Scientific Committee of the Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n, and all participants signed an informed consent form. Forty-five healthy, surgically sterilized women, aged 29 years to 35 years old (mean age 31 years), with regular menstrual cycles (cycle lengths between 25 days and 32 days) were recruited for this study. None had used hormonal contraception or any other medication within 6 months prior to the study. Participants were in good health as determined by medical history, physical examination, and routine screening laboratory tests, including Papanicolaou smear. Body weight, height, and blood pressure of each participant were registered by one investigator. Participants were issued a menstrual calendar on which they recorded details of all bleeding episodes throughout the study.

The study was conducted in two consecutive cycles. Cycle was defined as the time elapsed from the first day of a spontaneous menstrual bleeding until the day preceding the next menses. All participants were admitted during the first 10 days of their menstrual cycle. Before the control cycle, women were randomly allocated into three different groups as follows: Group A women received two doses of 0.75 mg LNG (Postinor, Gedeon Richter, Budapest, Hungary) taken 12 h apart, with the first dose given on the morning of day 10 of the menstrual cycle; Group B women received the same dose of LNG immediately after positive LH detection in urine; and Group C women received the same dose of LNG 48 h after positive detection of urinary LH. During both cycles (control and treated), all women were asked to monitor urinary LH every morning, starting on the 11th day of the menstrual cycle until the presence of LH was detected. At this time, transvaginal ultrasound was performed daily until follicle rupture (FR) was observed. This was established by the presence of at least three of the following findings: acute decrease in mean diameter or disappearance of the follicle, presence of thickened irregular borders, increased echogenecity within the follicle, and presence of free intraperitoneal fluid [16]. At each follow-up visit, ultrasound was performed by the same observer using a SSD-2000 ultrasonographic equipment (Aloka Co. Ltd., Wallingford, CT, USA). Women who did not present positive LH in urine and FR during the control cycle were excluded from the study. Daily blood samples were obtained from the day of positive LH detection in urine until the day menses began. All samples were centrifuged, and serum was stored at _20°C until assayed. Serum progesterone (P4) and estradiol (E2) concentrations were determined in all samples, whereas serum LH was quantified only from the day of detected urinary LH until P4 serum concentrations reached at least 3 ng/mL. The main purpose for measuring serum LH was to precisely determine, rather than based only on urinary LH detection, the actual time at which LNG was administered during the menstrual cycle. Follicular phase was considered from the first day of bleeding until the day of maximum serum LH concentrations and the luteal phase from the next day of serum LH surge until the day before menses began. In addition, endometrial biopsies were taken from all participants during both control and treated cycles on day LH _ 9. This day lies within the implantation window, the time during which the endometrium has optimal receptivity to implantation [17,18]. Endometrial tissues were obtained with a Novak curette from the anterior wall of the uterine cavity without dilatation of the cervix or local anesthesia. Biopsy specimens were immediately fixed in formalin solution and used for light microscopic examination after embedding in paraffin and staining with hematoxylin and eosin. Biopsy specimens were read blindly to the examiner for histologic dating.

LH in urine was monitored by a commercially available kit (Ovuquick, Corne SA de CV, Mexico) that is predictive for follicular collapse in 73% and 92% of cases, within 24 to 48 h, respectively, after positive urinary LH testing [19]. Serum concentrations of LH, E2, and P4 were measured in duplicate by specific immunoradiometric assay for LH and specific radioimmunoassays for E2 and P4 by using commercial reagents (Diagnostic Products Corporation, USA) and protocols provided by the World Health Organization Matched Reagent Programme (Geneva, Switzerland) as previously described [20,21]. The interassay coefficient of variation (CV) was less than 10% for all hormones, and intraassay CV were 4.9%, 1.63%, and 1.33% for LH, E2, and P4, espectively. These CVs were calculated from pools of standard sera at the average hormone concentrations of 16.1 mIU/mL, 50 pg/mL, and 1.5 ng/mL for these hormones, respectively. To avoid interassay variations, all samples corresponding to the same individual were measured within the same assay.

Endometrial morphology was assessed by correlating the chronological date (day after LH surge) with the morphological endometrial characteristics of specimens as an indicator of hormone action. The dating of the endometrium was related to the serum LH surge, FR, and luteal concentrations of E2 and P4, rather than to the “ideal” 28-day cycle, as previously described [22]. The parameters examined were number of glands, stromal edema, and predecidual changes as evaluated by the presence of prominent spiral arteries. The readings of specimens were made blindly by the same morphologist, who had no knowledge of either the day of the cycle at which biopsy was taken nor the treatment instituted. Histologic dating was performed using criteria described by Noyes et al. [23] and by Hendrickson and Kempson [24]. Glandular and stromal elements were dated separately and given equal importance, as described by Lessey et al. [25]. A specimen in which glandular maturation was delayed by 3 or more days from the day calculated from the date of LH surge was defined as to be “out of phase” [26].

The analysis compared the differences of integrated luteal E2 (ILE2), integrated luteal P4 (ILP4), cycle characteristics, and endometrial morphology between the control and treated cycles. ILE2 and ILP4 were analyzed by calculating the area under the curve (AUC) for both hormones during the luteal phase of the control and treated cycles. The AUC was calculated for 9 days after serum LH surge by the trapezoid method with the aid of a computer program. A log-normal distribution was assumed [27], and an unpaired sample t-test was used to evaluate the significance of differences (p _ 0.05) between each participant’s ILP4 and ILE2, daily hormone concentrations, cycle characteristics, and endometrial morphology in the control and treated cycles. A one-sided test was planned because the change in markers in treated cycles was expected to occur in only one direction [28]. An analysis of variance was used to report clinical characteristics.

The characteristics of the study population are given in Table 1. Examination of the distribution of the different variables revealed no significant differences among all women who were randomly allocated into the three treatment groups. Accordingly, all 45 control cycles were combined as only one reference group. All participants had ovulatory control cycles between 21 and 34 days with luteal phase lengths from 9 to 15 days, with evidence of FR within 11 and 21 days from the first day of the cycle. Maximal serum luteal P4 concentrations were observed at day 21 _ 3 and mean ILP4-AUC was 90.3 _ 41.1 ng/mL for 9 days after serum LH surge (Table 2 and Fig. 1).

Timing comparisons between serum with urinary LH demonstrated inconsistencies in 12 out of 90 studied cycles (13.3%). In four control cycles (8.8%) and eight treated cycles (17.7%), urinary LH did not correlate with the day of maximum concentrations of serum LH. In these cases, serum LH, along with E2 and P4 concentrations, were used rather than urinary LH for cycle dating. Thus, eight participants during the treated cycle were identified as not corresponding to the originally assigned groups. Therefore, in four participants originally included in Group B and four in Group C, the administration of LNG took place 3 _ 1 day prior to serum LH surge and were reassigned into a new group (Group D). This new group received LNG during the late follicular phase, a few days prior to the occurrence of the LH surge. Thus, the groups studied consisted finally of 15 participants in Group A, 11 in Groups B and C, and 8 in Group D.

Twelve participants of Group A did not ovulate, and LNG significantly (p _ 0.05) shortened the mean length of the cycle compared to that of control (15 _ 2 vs 26 _ 3 days). These participants were, therefore, excluded from the remainder of the analysis. In the three remaining participants of Group A, LNG administration did not modify significantly the length of the cycle (28 _ 6 days), as shown in Table 2. In Groups B, C, and D, no modifications were noted on cycle length (27 _ 2, 26 _ 1, and 24 _ 5 days, respectively). Follicular phase length was significantly longer only in the three ovulatory participants of Group A (19 _ 2 vs 15 _ 3 days, p _ 0.05). In the remaining groups, no differences were observed in follicular phase length between the treated and control cycles (Table 2). In all participants of Groups B and C, there were no differences in luteal phase length between the treated and control cycles. The three LNG-treated participants with normal cycle length in Group A and all treated participants in Group D had a significant shortening (9 _ 4 and 10 _ 4 days, respectively) of the luteal phase (Table 2).

As was mentioned, 12 participants of Group A had anovulatory cycles following LNG, as evidenced by the absence of urinary LH and ultrasonographic findings of FR and the occurrence of endometrial bleeding within 6.3 _ 1.9 days (range 4–11 days) after treatment. The three ovulatory participants in Group A had a delayed positive test for LH in urine, which was further corroborated by measurements of serum LH and FR (Table 2). All participants in Groups B, C, and D had ultrasonographic findings of FR, and LNG administration did not modify the day of the cycle at which FR occurred (16 _ 2, 16 _ 2, and 15 _ 2 days vs 15 _ 2 days, respectively) (Table 2).

Fig. 1 depicts daily serum concentrations of P4 as well as ILP4 from treated and control cycles. As previously mentioned, only three participants of Group A ovulated following detection of urinary/serum LH and ultrasonographic evidence of FR. Although daily serum P4 concentrations and ILP4-AUC values in these participants did not reach statistical difference between the LNG-treated and control cycle, the mean serum ILP4-AUC obtained (44.7 _ 26.7 ng/mL/9 days) was notably lower than that observed in control cycles (90.3 _ 41.1 ng/mL/9 days). On the other hand, no changes were observed in serum ILE2-AUC during the luteal phase between treated (1083 _ 744 pg/mL/9 days) and control cycles (989 _ 385 pg/mL/9 days).

As already mentioned, all participants in Groups B, C, and D ovulated. With the exception of Group D, the mean serum ILP4-AUC in all remaining groups was similar when compared with the control cycle (Fig. 1). In Group D, participants presented significantly lower daily serum P4 concentrations and ILP4-AUC when compared with those in control cycles (15.9 _ 10.6 ng/mL/9 days vs 90.3 _ 41.1 ng/mL/9 days, respectively). No significant changes in ILE2-AUC were observed in all groups (Table 2).

In both control and treated cycles, neither inflammatory, reactive, nor other abnormal features in tissue specimens were observed. As shown in Table 3, with the exception of four insufficient endometrial specimens taken during the control cycle, endometrial morphology corresponded, according to both LH surge and FR, to the expected day (LH _ 8.6 _ 1.3 days) at which the biopsy was obtained. The results were highly consistent with the chronological date of sampling because differences longer than 3 days between the histologic diagnosis and the day of the cycle were not observed. A total of 24 out of 33 biopsies from treated cycles with ovulatory features were studied. The rest were excluded because of insufficient tissue sample (one from Group B and D) or because sampling did not correlate with the cycle day (three from Group A and four from Group D). Table 3 summarizes the morphological findings in Groups B, C, and D. No significant changes were observed between treated and control specimens in any of the studied parameters. No significant differences among groups were observed. Of particular importance was the finding that the predecidual changes as evaluated by the presence of prominent spiral arteries, which are considered crucial for implantation [24], were not altered by LNG.

Our study investigated the effects of short-term administration of LNG on ovulation and luteal phase function in ovulatory women with tubal ligation. Results were consistent with other studies showing that preovulatory administration of LNG alone or in combination with estrogens suppresses ovulation in most but not all cases [5, 29]. We could not, otherwise, 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.

A highlight in this study was the possibility to identify the exact cycle day of LNG administration, particularly relative to the midcycle serum gonadotropin surge. Serum LH measurements helped us to assess the day of ovulation, adding a new dimension to data interpretation of our study. Urinary LH proved to be a poor guide to determine the day of ovulation, yielding 13.3% false positives (true LH surge in serum occurred later in the cycle). This observation may explain inconsistencies found in a variety of studies on the effects of acute and timed administration of steroids on the menstrual cycle based only on urinary LH. In addition, this study also provides information on the effects of LNG on endometrial morphology during the implantation window.

Postcoital steroid administration is a well recognized, safe, and effective means of preventing pregnancy [4–14]. Limited information, however, exists on the mechanisms by which postcoital LNG achieves its contraceptive effect. The few studies on the contraceptive mechanisms of LNG suggest that in EC it may have, depending on the time of administration during the cycle, a wide spectrum of actions affecting steps from follicular growth and development, midcycle gonadotropin surge and ovulation, to corpus luteum and endometrial function [10,12,13,30–32]. Interestingly, in previous studies, LNG administered during the luteal phase revealed no alterations on either cycle length or endometrial morphology [12,13]. In the present study, ovulation was suppressed in 80% of participants receiving LNG during the follicular phase (Group A). On the contrary, 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 follicular maturation leading to deficient E2 and P4 production during the follicular and luteal phase, respectively.

In this regard, P4 has been involved in follicle atresia by a mechanism leading, in part, to reduction in the content and bioavailability of insulin-like growth factor I [33]. Furthermore, there is also evidence supporting the suppressive effects of progestins on follicle stimulating hormone (FSH)-stimulated E2 production by cultures of granulosa cells [34,35], including the in vivo inhibitory effects of P4 on follicular development even in the presence of elevated serum levels of FSH [36]. In addition, LNG administration to cycling cynomolgus monkeys [37] significantly decreased the serum levels of androstenedione, implying that estrogen precursors synthesis is also a target of LNG action at the ovarian level. 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. 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.

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 [38–40]. The finding of delayed ovulation following the administration of RU 486 just before midcycle LH surge [41] strongly supports these observations. It remains, however, unclear whether LNG by itself could induce the positive feed-back discharge of pituitary LH at this time of the cycle. 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 [42]. 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. Evidence that LNG might affect corpus luteum function through changes in LH pulsatile pattern prior to the triggering of LH surge in addition to, or rather than through, a direct action on P4 production can be encountered in other studies [43].

In this study, LNG administration to participants at the time of LH surge detection (Group B) or 48 h after LH surge (Group C) did not affect the overall P4 production or the length of the luteal phase. This finding agreed with the well known rise in P4 serum levels at the time and after the onset of the LH surge [40]. It is, therefore, possible to speculate that LNG, acting as a P4-like factor, should not disturb the process of follicular rupture and the formation of a normal corpus luteum. Indeed, in mice lacking P4 receptors, there is no evidence of ovulation and corpus luteum formation despite the presence of LH-exposed mature preovulatory follicles [44], indicating the important role of P4 in the process leading to follicular rupture and ovulation. These results also correlate with the presence of normal histopathological features in endometrial biopsies taken during the implantation window in women from Groups B, C, and D. Indeed, in this study, the process of transformation of endometrium into decidua, as a consequence of endometrial cell differentiation independently of conception occurred normally in women receiving LNG at the time or after the occurrence of LH surge. In this regard, the existence of edematous changes along with development of prominent spiral arteries in LNG-exposed tissues strongly suggest the apparent preservation of endometrial structures thought to be associated with implantation capabilities [45,46]. A successful implantation requires an adequate synchronization between embryo and endometrium development for invasion of spiral arteries by trophoblast cells [47]. These results suggest that postovulatory contraceptive efficacy of LNG may not involve alterations in the mechanisms associated with endometrial receptivity. A similar conclusion was reached by Raymond et al. [48], where no substantial evidence for the contraceptive effect of the Yuzpe regimen at the level of endometrium could be established.

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 mechanisms involved in LNG actions 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. 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.

The authors thank Dr. Ma. Eloisa Dickinson who kindly helped with volunteers’ enrollment, Dr. Enrique Sampedro-Carrillo for endometrial evaluations, Mr. Porfirio Robles for his technical assistance in data analysis, and Gedeon Richter, Ltd. (Budapest, Hungary) for donation of the hormonal preparation. The authors gratefully acknowledge Dr. Charlotte Ellertson from the Population Council (Mexico) for helpful discussions during the preparation of this manuscript.

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In light of the over the counter status of Plan B that was announced today, this article needs to be posted where more can read and critique it.

This is just about as elegant a study as could be wished for. There may be other factors that could be looked at in order to assure that there are no post-fertilization effects on the embryo, and I have a wary, watchful waiting attitude about prescribing this medicine.

I certainly do not believe that it should be over the counter. But I'm the one who predicted doom when the H2 blocker antacid Prilosec went over the counter and I'm still waiting for resistant strains of Candida in response to the OTC anti-fungals. And don't get me started on the risks vs. benefits of OTC head lice treatments.

I haven't figured out how to post tables and figures, yet. Can anyone help?

The operant goal of this study was to arrive at the following conclusion (at the end of the article) because the reason for this study was to search how the medication achieves contraception and to eliminate implantation prevention as a mechanism for this product: "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." As stated, the study does not address other possible means by which this hormonal bolus prevents a pregnancy being achieved.

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.

That's kind of like saying that running an OBDII test on my Chevrolet Tahoe did not support a non-stopping effect of new brakes...

The test had no way of testing actual implantation. IN fact - when reading the entire test, we find that the test only really addressed chemical and hormonal effects, as well as limited testing of any changes (or lack thereof) to some tissues.

Nothing in the test was designed to disclude the possibility that this drug (basically a super dose of birth control pills) prevents implantation. It is all conjecture.

Just check the literature with Plan B - it specifies that it "may prevent the implantation of fertilized ovum".

So the study doesn's support nor dis-prove that method.

Nothing on pH, other than the vague reference to 'neither inflammatory or reactive'; nothing to correlate whether mucosal viscosity could prevent uptake of fluid by the embryo at the stage when building up inner fluid is crucial to development just prior to implantation. I will await further studies to clarify these issues. Thanks for posting the study, m'Lady.

As I have said before, I'm still not encouraging the use of this protocol because of the questions about implantation and I do not believe that Plan B should be OTC. This study is about as close as possible in humans to test the effects of a protocol on ovulatory women without risking actual embryos.

These results also correlate with the presence of normal histopathological features in endometrial biopsies taken during the implantation window in women from Groups B, C, and D. Indeed, in this study, the process of transformation of endometrium into decidua, as a consequence of endometrial cell differentiation independently of conception occurred normally in women receiving LNG at the time or after the occurrence of LH surge. In this regard, the existence of edematous changes along with development of prominent spiral arteries in LNG-exposed tissues strongly suggest the apparent preservation of endometrial structures thought to be associated with implantation capabilities [45,46]. A successful implantation requires an adequate synchronization between embryo and endometrium development for invasion of spiral arteries by trophoblast cells [47]. These results suggest that postovulatory contraceptive efficacy of LNG may not involve alterations in the mechanisms associated with endometrial receptivity. A similar conclusion was reached by Raymond et al. [48], where no substantial evidence for the contraceptive effect of the Yuzpe regimen at the level of endometrium could be established.

Studies in Cebus monkeys and rats have shown no interference in implantation of embryos.

In actual human usage, the pills are only effective about 70%-80% of the time, meaning that about 20% to 30% of the time, women do get pregnant.

I cannot get past the idea that lower dosages are available only by prescription because they are artififical hormonal systems, yet this bolus dosing is available OTC and will be ingested by very young females, yet science hasn't a clue what the longterm effects will be of disrupting the hormonal feedback mechanisms of young felmales! But then Murray and clinton don't actually give a damn about young females so long as they may be sacrificed in democrap empowerment schemes. Isn't she going to be just the right president for this degenerating nation? We deserve the swinehunt.

And in the meantime, I have to sign for my decongestants - Walmart's policy is even more strict than Texas' which is stricter than the Feds'. The result is that I couldn't get the maximum therapeutic dose, if I wanted to.

In the UK, Jamaica, and the study in California (the one that's always touted as showing that Plan B doesn't increase risky behavior. http://www.lifeethics.org/www.lifeethics.org/2006/08/plan-b-doesnt-change-much.html

This move, at this time, was bad politics, not good medicine or social policy.

Putting aside the moral implications vis-a-vis implantation for the moment, the most damning thing I've read is that it is ineffective and may have potentially serious side effects.

The massive Scottish study concluded that providing participants with the drug prior to unprotected sex had no effect on pregnancy or abortion rates. The British government also warned physicians that in cases of failed emergency contraception ectopic pregnancy rates were three-times the norm.

What were left with is a decision, made for purely political reasons, that angers a large segment of the President's base, has not been demonstarted to work and which may have serious medical consequences. Senseless.

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