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Sure, as long as we all agree about the politics OF insurance.

Can we talk about he-who-shall-not-be-named-Care that forced nuns to offer medical insurance that covers abortion?  Or can we talk about he-who-shall-not-be-named who overturned that mandate?  Can we even talk about that mandate?

Or can we talk about the mandate for people to buy health insurance or pay a fine?  How about how (insert-politicians name)-Care drove insurance prices up for everyone and caused the majority of counties in the US to have fewer insurance carriers, with 960 counties eventually only having ONE insurance carrier.

Can we talk about Medicare?  Can we talk about how a President (won't insert which one or his political party) lowered the insulin co-pay to $35 for those on  Medicare?

The list is long, and confusing.

Better to just ban the folks who can't be respectful and let the adults have a conversation.

Great discussion points.

At no point was there ever an abortion mandate in the ACA.  Ever.  This would be in violation of the Hyde amendment. The lawsuit I'm assuming you're bringing up in an incorrect manner would be the Little Sisters vs. Whoever when there was an objection to providing birth control.  Then there was an objection to providing a form saying that they don't provide birth control, as that would be "cooperating with evil".

https://www.ncronline.org/news/opinion/signs-times/little-sisters-poor-return-court-fight-birth-control-mandate

If you have sources detailing an abortion mandate for nuns I would enjoy reading it and seeing how it wasn't trumpeted from the mountaintops.

 

Can you detail what you dislike regarding the individual mandate? I'm assuming it is in regards to personal choice, but should that apply in healthcare when the costs of the uninsured are passed on to those who have insurance?

I concur that costs have continued to rise, and due to those costs the average healthy individual left the individual insurance markets.  What is your solution to the healthcare insurance problem facing the country? I recall some back 'n forths in the past where you have a strong stance that access to healthcare shouldn't be considered a right?

 

In regards to the much touted $35 insulin co-pay...

"The Administration’s new model that allows participating Part D plans to cap monthly out-of-pocket insulin costs could help some beneficiaries with their insulin costs, if they are enrolled in a participating Part D plan and use an insulin product covered by their plan with a $35 copayment. But the new model applies to a subset of plans and enrollees (those without low-income subsidies in enhanced plans, which cover 80% of non-LIS Part D enrollees in non-employer Part D plans in 2020), and not all insulin products have to be covered by all participating plans. The new model also does not address underlying list price increases for insulin or affordability concerns for people who are uninsured or covered by other sources of coverage."

Other nice points from the analysis include:

- Voluntary participation by the Medicare Part D plans, not required (although reportedly enrollment looks robust for 2021)

- You have to buy the "enhanced" plan, which ends up costing ~$200 more a year, offsetting the proposed savings of the new insulin copay (~$160)

- Only required to offer the copay on one brand of each insulin (if you've ever transitioned a patient from one to another it can be rough...plus seems an awful lot like mandating a certain brand over another potentially)

https://www.kff.org/medicare/issue-brief/insulin-costs-and-coverage-in-medicare-part-d/

 

I've answered these talking points as if they were made in all seriousness, if you had meant them in jest or hyperbolic I apologize for taking you seriously. 

 

 

 

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I give this discussion just a few hours before some of the children come out and interrupt the adults with insults and then the mods once again close it down.

First, I was being slightly hyperbolic because my post was about letting such respectful discussions TAKE PLACE, not about the topics itself, but here goes...

2 hours ago, MediMike said:

At no point was there ever an abortion mandate in the ACA.  Ever.  This would be in violation of the Hyde amendment. The lawsuit I'm assuming you're bringing up in an incorrect manner would be the Little Sisters vs. Whoever when there was an objection to providing birth control.  Then there was an objection to providing a form saying that they don't provide birth control, as that would be "cooperating with evil".

No, the ACA did not require insurance to provide abortion PROCEDURES, although it required insurances to follow state rules and I think many states did require it.  However to many people of faith the "plan B" is considered an abortion which was covered under the ACA (and hence the lawsuit from the nuns).

The Hyde amendment would not prevent this.  States which provided funds for abortions through the ACA would have just claimed that those funds came from the state instead of the federal government (much like Planned Parenthood does).

 

2 hours ago, MediMike said:

Can you detail what you dislike regarding the individual mandate?

My greatest dislike for this is that it is the government telling you that you MUST purchase something.  This is blatantly unconstitutional, but was made constitutional by the Roberts court who said it was a tax....but that ignores the constitutional requirement for tax bills to start in the House, not the Senate where the ACA was launched.  


And yes, I understand that the insulin changes only affect a few.  I have not done a deep dive into that, but I would guess that Trump is doing what he legally can.  Despite his good intentions, I disagree with such executive orders in general.

 

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2 hours ago, Boatswain2PA said:

No, the ACA did not require insurance to provide abortion PROCEDURES, although it required insurances to follow state rules and I think many states did require it.  However to many people of faith the "plan B" is considered an abortion which was covered under the ACA (and hence the lawsuit from the nuns).

The Hyde amendment would not prevent this.  States which provided funds for abortions through the ACA would have just claimed that those funds came from the state instead of the federal government (much like Planned Parenthood does).

I had forgotten that Sotomayor had to issue a stay on that to allow the lawsuit to go through, the Plan B thing was what...2012? To my knowledge Plan B prevents fertilization, it's like outlawing menstruation but I digress.

I'm not sure I follow you on the second paragraph, are you saying that the Hyde amendment should be done away with since it serves no purpose or that no funds at all should be allowed to be used? I figured a proponent of states' rights and less federal involvement would prefer that the state be able to utilize their funds for their own purposes? <Not a dig, just trying to understand>

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Plan B prevents implantation AFTER fertilization, which many people of faith think is equivalent to purposely killing a baby (an abortion).

I personally think abortion should be banned in general.  Regarding the Hyde amendment, if we didnt have that then when the Dems get control of the WH again we will see even more federal money going to pay for abortions.

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2 hours ago, MediMike said:

I had forgotten that Sotomayor had to issue a stay on that to allow the lawsuit to go through, the Plan B thing was what...2012? To my knowledge Plan B prevents fertilization, it's like outlawing menstruation but I digress.

56 minutes ago, Boatswain2PA said:

Plan B prevents implantation AFTER fertilization, which many people of faith think is equivalent to purposely killing a baby (an abortion).

I personally think abortion should be banned in general.  Regarding the Hyde amendment, if we didnt have that then when the Dems get control of the WH again we will see even more federal money going to pay for abortions.

 

CBA3B241-C661-4A50-BDF9-F440A8D69981.png

We can talk about the science, but let’s not talk about abortion and if we should or should not be performing it from a religious point of view. Data only. Just asking for the thread to be killed.

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We should be able to respectfully talk about anything.  Medical ethics is important to our field, and abortion is obviously fraught with ethical challenges.

Regarding Plan B (2 pills of progesterone (levonorgestrel) only).  It once was widely understood that likely worked by preventing implantation (https://www.aafp.org/afp/2000/0501/p2605.html is old opinion piece that referenced the PDR about this).

From my 2011 "CURRENT Medical Diagnosis and Treatment" book that I have handy, page 749, it says "If unprotected intercourse occurs in midcycle and if the woman is certain she has not inadvertently become pregnant earlier in the cycle, the following regimens are effective in preventing IMPLANTATION (emphasis mine).  These methods should be started as soon as possible and within 120 hours after unprotected coitus.  (1) Levonorgestrel, 1.5mg orally as a single dose (available in the United states prepackaged as Plan B and available over-the-counter ffor women aged 17 years and above), has a 1% failure rate, when taken within 72 hours."

So, in 2011 published books it shows we clearly thought levonorgestrel prevented IMPLANTATION, and a 2000 era opinion piece listed the PDR as saying it likely did.  

If you google/bing search for "how does levonorgestrel prevent implantation" you get no results for that, but rather pages of mostly opinion pieces saying that "oh no, it prevents fertilization".  

So, what changed?  Do we have new science behind this?  Or is this another example of how politics infects every single thing we do, especially the sources we get information from.

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8 hours ago, LT_Oneal_PAC said:

CBA3B241-C661-4A50-BDF9-F440A8D69981.png

We can talk about the science, but let’s not talk about abortion and if we should or should not be performing it from a religious point of view. Data only. Just asking for the thread to be killed.

Hence why Plan B is written to be taken ASAP after unprotected intercourse, up to 72h to be most efficacious to prevent fertilization.

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27 minutes ago, SedRate said:

Hence why Plan B is written to be taken ASAP after unprotected intercourse, up to 72h to be most efficacious to prevent fertilization.

Yet we knew <72 hour administration was more efficacious back when textbooks said it prevented implantation.

From the article you posted:
"Official statements from the International Consortium for Emergency Contraception (ICEC), the Federation of Gynecology & Obstetrics (FIGO), and the American College of Obstetrics and Gynecology (ACOG) have repeatedly claimed that LNG-EC pills work with a dominant mode of ovulation suppression, asserting for example in multiple FIGO's statements that “inhibition or delay of ovulation is LNG-EC pills’ principal and possibly only mechanism of action” (FIGO 2011; International Federation of Gynecology & Obstetrics (FIGO) and International Consortium for Emergency Contraception (ICEC) 2012; ACOG 2014). Our findings confirm and extend earlier reviews of the topic suggesting that post-fertilization MOA of LNG-EC play a not negligible and possibly dominant role (Peck and Velez 2013; Mozzanega and Cosmi 2011; Kahlenborn, Stanford, and Larimore 2002)."

In medicine we frequently practice according to best practices & policies published by "expert" organizations like the AHA, ACOG, etc.  But when we do this should not be blind to the bias of the organizations who set the practices/policies. 

Anyone really think the "International Consortium for Emergency Contraception" would not be a little biased toward massaging the message about Plan B?  I don't know about FIGO, but ACOG is also a very "progressive" organization.

From:  https://pubmed.ncbi.nlm.nih.gov/11895061/ "The available evidence for a postfertilization effect is moderately strong, whether hormonal EC is used in the preovulatory, ovulatory, or postovulatory phase of the menstrual cycle."

"

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2 hours ago, Boatswain2PA said:

Yet we knew <72 hour administration was more efficacious back when textbooks said it prevented implantation.

From the article you posted:
"Official statements from the International Consortium for Emergency Contraception (ICEC), the Federation of Gynecology & Obstetrics (FIGO), and the American College of Obstetrics and Gynecology (ACOG) have repeatedly claimed that LNG-EC pills work with a dominant mode of ovulation suppression, asserting for example in multiple FIGO's statements that “inhibition or delay of ovulation is LNG-EC pills’ principal and possibly only mechanism of action” (FIGO 2011; International Federation of Gynecology & Obstetrics (FIGO) and International Consortium for Emergency Contraception (ICEC) 2012; ACOG 2014). Our findings confirm and extend earlier reviews of the topic suggesting that post-fertilization MOA of LNG-EC play a not negligible and possibly dominant role (Peck and Velez 2013; Mozzanega and Cosmi 2011; Kahlenborn, Stanford, and Larimore 2002)."

In medicine we frequently practice according to best practices & policies published by "expert" organizations like the AHA, ACOG, etc.  But when we do this should not be blind to the bias of the organizations who set the practices/policies. 

Anyone really think the "International Consortium for Emergency Contraception" would not be a little biased toward massaging the message about Plan B?  I don't know about FIGO, but ACOG is also a very "progressive" organization.

From:  https://pubmed.ncbi.nlm.nih.gov/11895061/ "The available evidence for a postfertilization effect is moderately strong, whether hormonal EC is used in the preovulatory, ovulatory, or postovulatory phase of the menstrual cycle."

"

Yes, I read that. But as I already mentioned in my second post, the papers that are quoted as saying that it's post-fertilization (bolded and italicized; one of which, I think the one by Peck and Velez, was published in The National Catholic Bioethics) are review articles of other review articles, which are low-quality data. Since Plan B isn't really relevant to my practice in trauma surgery, I don't care to do a deeper dive into the reviews of other reviews to finally find the actual data being referenced. Hence my second question, which was if someone was able to find the actual scientific data referenced for these claims. 

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2 hours ago, Boatswain2PA said:


From:  https://pubmed.ncbi.nlm.nih.gov/11895061/ "The available evidence for a postfertilization effect is moderately strong, whether hormonal EC is used in the preovulatory, ovulatory, or postovulatory phase of the menstrual cycle."

"

This is yet again another review article which is low quality data and of articles from 1966-2001. 

"Although both methods sometimes stop ovulation, they may also act by reducing the probability of implantation, due to their adverse effect on the endometrium (a postfertilization effect)."

"Based on the present theoretical and empirical evidence, both the Yuzpe regimen and Plan B likely act at times by causing a postfertilization effect, regardless of when in the menstrual cycle they are used."

That's a lot of what ifs and maybes. Where are the data?

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I dont think it's possible to get that data.  We have no way of knowing if fertalization has occurred until implantation and then the rise in bHCG.  Before that we have no data, just theories of how the hormone works on what cells/receptors (of course based on in vitro testing).

I dont see what has changed science-wise though from 2000-2010 and today, which makes me suspect it is more political massaging of what we know (all of those ifs and maybes).

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22 minutes ago, Boatswain2PA said:

I dont think it's possible to get that data.  We have no way of knowing if fertalization has occurred until implantation and then the rise in bHCG.  Before that we have no data, just theories of how the hormone works on what cells/receptors (of course based on in vitro testing).

I dont see what has changed science-wise though from 2000-2010 and today, which makes me suspect it is more political massaging of what we know (all of those ifs and maybes).

Sure. Sadly, the evidence for implantation effect is limited to poor quality data and theory. The medication is intended for immediate use after unprotected intercourse up to 72h, which is to prevent fertilization and therefore implantation. Are you implying this medication shouldn't be prescribed after 72h?

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9 minutes ago, SedRate said:

intended for immediate use after unprotected intercourse up to 72h, which is to prevent fertilization and therefore implantation.

Yes, this is what the medication insert, FDA, and specialty organizations say today.

 

But 10 years ago they were not saying it prevented fertilization but rather implantation.  How has the science changed?  Doesnt seem like it has, which makes me suspect politics.

9 minutes ago, SedRate said:

Are you implying this medication shouldn't be prescribed after 72h?

Not sure where you are getting this, but no.  

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9 minutes ago, Boatswain2PA said:

Yes, this is what the medication insert, FDA, and specialty organizations say today.

 

But 10 years ago they were not saying it prevented fertilization but rather implantation.  How has the science changed?  Doesnt seem like it has, which makes me suspect politics.

Not sure where you are getting this, but no.  

From your second article published in a Pharm journal in 2002 based off of articles collected from 1966-2001:

"Although both methods sometimes stop ovulation, they may also act by reducing the probability of implantation, due to their adverse effect on the endometrium (a postfertilization effect)."

So, no, the science didn't change. And yes, they actually did say it prevented fertilization by stopping ovulation from what they gathered from articles written between 1966-2001, just as they are reasserting in 2011-2012 in your post further above.

Sadly, we're basing this off of poor quality data from review articles and not actual data, so I digress. 

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5 minutes ago, Boatswain2PA said:

Yeah, I agree.  I think we are obligated to tell anyone we rx this to that it may work through inhibiting implantation as many people of faith think that would be wrong.

...And also by preventing ovulation and thus fertilization. What should also be discussed is that unprotected sex can result in pregnancy, abstinence prevents pregnancy, and condoms prevent both pregnancy and STDs 😉

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3 hours ago, Boatswain2PA said:

I find myself saying that A LOT.  I think meth is a much larger problem in the US than 'Rona.  Last shift had a 4 yo who, if they live, will have lifelong disability almost assuredly due to mom & dads meth. 

Depending on which ED I'm working in, between 25-50% of my patients are there as a result of meth.

Agreed. It's insane how common it is. And unfortunate to see it in kids and pregnant women. 

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Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials of emergency contraception regimens.
AU
Brache V, Cochon L, Deniaud M, Croxatto HB 
SO
Contraception. 2013;88(5):611. Epub 2013 May 22. 
 

BACKGROUNDThe days just prior to ovulation are the most crucial for emergency contraception (EC) efficacy. Ulipristal acetate (UPA) and levonorgestrel's (LNG) capacity to inhibit follicular rupture have never been compared directly at this time of the cycle.

STUDY DESIGNRaw data from three pharmacodynamics studies with similar methodology were pooled to allow direct comparison of UPA, LNG and LNG + meloxicam's ability to prevent ovulation when administered orally in the advanced follicular phase, with a leading follicle of≥18 mm.

RESULTSForty eight LNG-treated (1.5 mg) cycles, 31 LNG (1.5 mg) + meloxicam (15 mg), 34 UPA (30 mg) cycles and 50 placebo cycles were compared. Follicle rupture was delayed for at least 5 days in 14.6%, 38.7%, 58.8% and 4% of the LNG-, LNG + meloxicam-, UPA- and placebo-treated cycles, respectively. UPA was more effective than LNG and placebo in inhibiting follicular rupture (p = .0001), while LNG, when administered at this time of the cycle, was not different than placebo. The addition of meloxicam improved the efficacy of LNG in preventing follicular rupture (p = .0292 vs. LNG; p = .0001 vs. placebo; non-significant vs. UPA). UPA was effective in preventing rupture in the 5 days following treatment, even when administered at the time of the luteinizing hormone (LH) surge (UPA 79%, LNG 14% and placebo 10%). None of the treatments were effective when administered on the day of the LH peak. The median time from treatment to rupture was 6 days during the ulipristal cycles and 2 days in the placebo and LNG/LNG + meloxicam cycles (p = .0015).

CONCLUSIONAlthough no EC treatment is 100% effective in inhibiting follicular rupture when administered in the late follicular phase, UPA is the most effective treatment, delaying ovulation for at least 5 days in 59% of the cycles. LNG is not different from placebo in inhibiting follicular rupture at this advanced phase of the cycle. No treatment was effective in postponing rupture when administered on the day of LH peak.

AD
PROFAMILIA, Santo Domingo, Dominican Republic. Electronic address: vbrache@gmail.com. 
PMID
23809278
 
 
4
 | | PubMed
TI
Emergency contraception -- mechanisms of action.
AU
Gemzell-Danielsson K, Berger C, P G L L 
SO
Contraception. 2013 Mar;87(3):300-8. Epub 2012 Oct 29. 
 

Concerns regarding the mechanisms of action of emergency contraception (EC) create major barriers to widespread use and could also lead to incorrect use of EC and overestimation of its effectiveness. While the copper intrauterine device (Cu-IUD) is the most effective method available for EC, the hormonal methods are frequently considered to be more convenient and acceptable. Today, the most commonly used method for hormonal EC is levonorgestrel (LNG). More recently, the progesterone receptor modulator ulipristal acetate (UPA) has been shown to be more effective than LNG to prevent an unwanted pregnancy. The main mechanism of action of both LNG and UPA for EC is delaying or inhibiting ovulation. However, UPA appears to have a direct inhibitory effect on follicular rupture which allows it to be effective even when administered shortly before ovulation, a time period when use of LNG is no longer effective. The main mechanism of action of the Cu-IUD is to prevent fertilization through the effect of Cu ions on sperm function. In addition, if fertilization has already occurred, Cu ions influence the female reproductive tract and prevent endometrial receptivity. Based on this review of the published literature, it can be concluded that existing methods used today for EC act mainly through inhibition of ovulation or prevention of fertilization.An additional effect on the endometrium as occurs for the Cu-IUD, but not for the hormonal alternatives, seems to increase the efficacy of the method.

AD
Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet/ Karolinska University Hospital, S-171 76 Stockholm, Sweden. kristina.gemzell@ki.se 
PMID
23114735
 
 
5
 | | PubMed
TI
Does ulipristal acetate emergency contraception (ella®) interfere with implantation?
AU
Li HWR, Resche-Rigon M, Bagchi IC, Gemzell-Danielsson K, Glasier A 
SO
Contraception. 2019;100(5):386. Epub 2019 Jul 24. 
 

BACKGROUNDUlipristal acetate (UPA) 30 mg (ella®, HRA-Pharma, Paris, France) acts as an emergency contraceptive (EC) by delaying ovulation. Because it is a selective progesterone receptor modulator, an additional effect on interfering with implantation has been suggested.

OBJECTIVEThis review discusses the evidence for, and against, an anti-implantation effect of UPA-EC.

SOURCES OF EVIDENCEPrimary research on the effect of UPA, at a relevant dose, on endometrium, implantation, efficacy and pregnancy outcome.

RESULTSUPA-EC does not appear to have a direct effect on the embryo. Changes in endometrial histology are small and not consistent, varying among studies. While UPA-EC affects the profile of gene expression in human endometrium, the findings vary between studies, and it is not clear that these changes affect endometrial receptivity or prevent implantation. UPA at pharmacological concentrations does not appear to have any inhibitory effect on embryo attachment in in vitro systems of human endometrium. UPA-EC is not more effective at preventing pregnancy than chance alone if used after ovulation and does not increase miscarriage rates.

CONCLUSIONSAn anti-implantation effect of UPA is highly unlikely at the dose used for EC. Maintaining the warning on the FDA-approved label that "it may also work by preventing implantation to the uterus" might deter some women from using EC, leaving them no option to prevent unwanted pregnancy after unprotected sexual intercourse.

AD
 
PMID
31351035
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1.1.1

Effect of UPA on the preimplantation embryo

Evidence from animal studies shows no effect of UPA on early embryo development. Gómez-Elías and coworkers (2016) injected UPA (40 mg/kg), or vehicle only, into superovulated female mice caged with proven fertile male mice just before or after mating [6] .The percentage of fertilized eggs recovered from the oviductal ampulla was not significantly different between UPA-treated animals and controls [6] . In the same study, zygotes were recovered from the mated female mice and cultured in vitro for 4 days in the presence or absence of UPA (1000 ng/mL). No difference was observed in the percentage of cleaving embryos or the cleavage speed [6] . While there are no such studies on human embryos, data from both clinical trials and postmarketing surveillance of UPA-EC [7] show no increased risk of early pregnancy loss (miscarriage) or teratogenesis in women who conceive following exposure to UPA-EC. Thus, an effect of UPA 30 mg on embryo viability seems unlikely.

1.1.2

Effect on endometrial histology, endometrial thickness and menstrual bleeding

A number of studies have investigated the effects of UPA, given to women at various times in the cycle, on endometrial histology and thickness. In contrast to all the clinical studies and to those on markers of endometrial receptivity, models of embryo attachment and the effect on the preimplantation embryo, all the studies investigating effects on the histology of the endometrium used nonmicronized preparations of UPA, while the marketed UPA-EC product is micronized. Micronization of the drug allowed reduction of the dose from 50 mg to 30 mg when used in tablet form; however, an indirect pharmacokinetic comparison confirmed the similarity of the two formulations. [8] Stratton and coworkers (2000) compared the effect of midfollicular phase administration of unmicronized UPA (10, 50 and 100 mg) versus placebo on endometrial histology [9] . UPA caused a significant dose-dependent decrease in endometrial thickness and a delay in maturation with all three doses. The delay in maturation was assessed by morphology based on Noyes criteria [10] . In this study [9] , the lag in endometrial development following exposure to UPA in the follicular phase likely reflects the delay in ovulation described by Brache et al. (2010) [1] : if ovulation is delayed by 5 days, one would expect endometrial maturation to be similarly delayed.

Passaro et al. (2003) evaluated the impact of unmicronized UPA at doses of 1–200 mg given to 36 women during the midluteal phase (LH+6 to +8) on luteal phase length and occurrence of bleeding [11] . While all subjects treated with unmicronized UPA 200 mg (several multiples of the dose used for EC) experienced early onset of vaginal bleeding indicating endometrial breakdown, lower doses did not alter cycle length; for all doses except 200 mg, the length of the luteal phase was not different from that of women treated with placebo. A decline in serum progesterone concentration suggested early luteolysis in 4 of 30 women (just 13.3%) treated with up to 100 mg UPA.

In a third study, Stratton et al. (2010) evaluated the effects on the endometrium of unmicronized UPA (10, 50 and 100 mg) administered during the early luteal phase (LH+1 or +2) in 55 healthy women [12] . This timing of administration is arguably most appropriate for investigating any theoretical effect of UPA on implantation. In contrast to their previous study in which UPA was given during the follicular phase [9] , Stratton et al. (2010) reported that administration of unmicronized UPA in the early luteal phase did not delay endometrial maturation compared to placebo. This supports the view that the delayed endometrial development shown in their previous study was most likely secondary to postponement of ovulation. Endometrial thickness was measured by ultrasound on the day of treatment and again on the day of the biopsy (4–6 days following UPA administration). Although there was a statistically significant change (p<.007) in endometrial thickness, the mean change was small in magnitude in both placebo-treated women (+1.3±2.3 mm) and UPA-treated women (−0.6±2.2 mm). Compared with placebo, increased progesterone receptor staining in glandular tissue was reported only among women treated with the higher doses of UPA (100 mg). At the 50-mg and 100-mg doses, decreased L-selectin ligand expression, thought to reflect endometrial receptivity [13] , was detected. Stratton et al. (2010) suggested that the changes noted in the higher doses “may be the earliest features of the anti-progestational effect… in the luteal phase, heralding other endometrial changes.” The effects of the lower doses of UPA were minimal.

While these data suggest that UPA does, expectedly, result in some dose-dependent effects on the endometrium particularly at doses higher than that used for EC, they shed no light on the clinical implications of such effects or on the receptivity of the endometrium to implantation of the human embryo in the EC context. Moreover, the usefulness of histology in determining endometrial “normality” has been called into question as histological delay in endometrial maturation fails to distinguish between fertile and infertile couples and is not accurate in distinguishing cycle days 14151617 . Indeed, a recent study of the endometrial receptivity “meta-signature” stated that “traditional endometrial dating criteria, like tissue histology, are obsolete since their accuracy, reproducibility and functional relevance have been questioned in various randomized studies” [18] .

1.1.3

Effect on markers of endometrial receptivity

The lack of clinical relevance of studies related to endometrial histology raises the possibility that examination of the biochemical and/or molecular profiles of the endometrium could be more meaningful. Acknowledging the challenges and complexity of obtaining and analyzing “normal” human samples, it has been suggested that such approaches may identify abnormalities in the endometrium which may predispose to abnormal implantation [18] .High-density microarray screening has been used to investigate changes in endometrial gene expression following exposure to UPA 30 mg. Fourteen healthy women with regular menstrual cycles were studied during 14 control cycles and 12 cycles treated with a single dose of 30 mg UPA when follicle diameter had reached 20 mm (at which time UPA would not be expected to delay ovulation) [19] . Ovulation in both treated and control cycles was confirmed by serum LH, progesterone and vaginal ultrasound. An endometrial biopsy was taken at day LH+7 in each cycle to isolate RNA for microarray and qPCR analysis, or for histology and immunohistochemistry. Analysis of the endometrial gene expression profile from UPA-treated and control cycles showed differential expression of PAEP and LIF, genes that are potentially linked to receptivity [20] .While PAEP, a progesterone-regulated gene thought to be important for attachment of the trophoblast to the endometrium [21] , was markedly down-regulated, down-regulation of LIF in the endometrial glands was modest in the UPA-treated group [19] . Further analysis of the same samples by the same group revealed down-regulation of PRL and STAT3 following UPA exposure [22] . Since these factors are involved in endometrial decidualization, the authors concluded that UPA 30 mg may affect the molecular mechanisms leading to endometrial decidualization.

While UPA affects the profile of gene expression in the endometrium, it is not at all clear that these changes affect endometrial receptivity or prevent implantation. In a review of tools to assess endometrial receptivity, Lessey (2010) concluded that the search for reliable biomarkers for the detection of abnormalities in endometrial receptivity “remains an elusive target” [23] . In a meta-analysis of the results of nine studies involving transcriptomic analysis of human endometrial samples covering the “pre-receptive” and “receptive” phases of the cycle, Altmae and coworkers (2017) stated that while hundreds of up- and down-regulated genes were theoretically involved in endometrial receptivity, the overlap between the studies was relatively small and potential diagnostic biomarkers had not been identified [18] . The limitations of the technology include differences in experimental design, timing and conditions of endometrial sampling, the type of patients/volunteers recruited, transcriptome array/sequencing platforms and genome annotation versions used, data processing and data presentation. In summary, the authors concluded that the role of differentially expressed genes in uterine physiology and pathophysiology remains to be investigated and, importantly, emphasized that none of the molecular markers have yet been successfully applied in clinical therapeutic practice. Whether the changes in endometrial gene expression associated with UPA 30 mg actually translate into any significant impact on endometrial receptivity and pregnancy establishment is uncertain and perhaps unlikely.

1.1.4

Effect on in vitro human embryo-endometrial attachment models

The histological and “omic” studies cited above all suffer from the same weakness, that is, they can only ever investigate human endometrium taken from “normal” volunteers (usually without any proven history of fertility), from women with clinical conditions known to be associated with infertility (such as endometriosis) or from women with a history of failure of implantation often diagnosed after failed assisted conception following transfer of apparently healthy or chromosomally normal embryos. It would be practically impossible to undertake a sufficiently large study involving biopsy of human endometrium in a cycle in which implantation is definitely going to take place (given the rate of successful implantation per cycle, the fact that women wanting to conceive would be extremely unlikely to participate, the fact that it would be considered an unethical study in women who did not want to conceive and the fact that it would be impossible to know whether the action of taking the biopsy and removing endometrial samples had affected implantation). Likewise, it is not possible to gain molecular insights from endometrium taken after successful implantation on the characteristics of the endometrium before implantation occurs (even if such investigations were ethically possible). Thus, while endometrium may look “abnormal” or may have an “abnormal” gene profile, we can never know in vivo whether it will support implantation should it be presented with a healthy fertilized embryo.

Recent studies addressing the attachment of human embryos to endometrial cells using in vitro models may come closest to providing direct evidence of the effects of ECs on endometrial receptivity. Berger and colleagues (2015) used endometrial biopsies from healthy women with proven fertility taken at LH+4 to create a three-dimensional human endometrial cell culture system [24] . Viable human blastocysts were randomly added to the cultures in the presence of UPA 0.4 μM ( n =10) or vehicle alone ( n =10), and attachment rate of the embryos to the endometrial cells was assessed. Exposure of the endometrial cells to UPA at a dosage equivalent to EC did not affect embryo viability, and importantly, there was no significant difference in the rate of embryo attachment between the UPA-treated and the control groups (p=.650).Using the same in vitro system and study design, the group had also reported no significant effect of levonorgestrel (LNG) 10 μM on human embryo attachment compared to control cultures (43% versus 59%) [25] ; this concurred with another two studies which demonstrated that postovulatory administration of LNG did not prevent pregnancy in monkeys [26] nor result in gene expression changes in human endometrium [27] . In contrast, mifepristone at doses of 10 μM or 0.5 μM (a dose lower to that shown to prevent pregnancy) did effectively inhibit embryo attachment in the three-dimensional in vitro co-culture model mentioned above [2528] .

In the Berger et al. study (2015), in addition to blastocyst attachment, the expression of a subset of genes known to be involved in endometrial receptivity was monitored in the in vitro endometrial cell culture system. [24] After removal of the blastocyst, total RNA was extracted from the day 3 cultures and real-time PCR analysis was performed with primers specific to 17 genes thought to be vital for endometrial receptivity and embryo implantation. The analysis revealed that out of these 17 genes, 2 were significantly up-regulated and 4 down-regulated; the majority remained unaltered after UPA exposure [24] .The profile of the up- or down-regulated genes after UPA treatment was quite different from that reported by Lira-Albarran et al. [19] whose study was done on human endometrium in normal cycles without exposure to embryo. The overall results from the in vitro model by Berger et al. (2015) suggest that the changes in endometrial gene expression identifiable after UPA exposure do not affect the attachment of the embryo to the endometrial cells.

Consistent with this notion, another study using a different in vitro model reported no effect of UPA on embryo attachment [29] . In this study, Li et al. (2018) co-cultured human endometrial cells with human trophoblastic spheroids (embryo surrogate) in the presence of UPA (0.04, 0.4 and 4 μM) or mifepristone (10 μM). While mifepristone significantly suppressed embryo attachment, UPA did not inhibit embryo attachment under the same condition. Collectively, these results indicate that UPA at pharmacological concentrations does not appear to have any interfering effect on embryo implantation in this in vitro system.

1.1.5

Evidence from clinical data

If UPA 30 mg had an effect on the establishment of pregnancy, it might be expected to increase the rate of miscarriage. However, analysis of all pregnancies reported during development and since the launch of ellaOne® in Europe and published in 2014 showed that 13.64% of the pregnancies with known outcomes ended in spontaneous miscarriage [7] , which was not different from the rate of spontaneous miscarriage reported in the general population. In a prospective study conducted on 700 Hong Kong women requesting EC within 120 h of unprotected intercourse, Li et al. (2016) showed UPA to be effective at preventing pregnancy if taken before ovulation had occurred but ineffective if taken after ovulation [30] . The time of the cycle was estimated using three parameters: cycle day (based on the date of the last menstrual period and length of the last three menstrual cycles); serum LH, estradiol and progesterone concentrations measured on the day of UPA intake; and the presence and size of the leading ovarian follicle measured by ultrasound on the day of UPA intake. The percentage of pregnancies prevented was calculated from the observed number of pregnancies and the number expected in the cohort using the Trussell formula [31] . A significantly lower pregnancy rate (p<.0001) was observed among women who received UPA before ovulation compared to the expected rate based on the Trussell formula. However, a significant difference was not similarly observed (p=.281) among those receiving UPA after ovulation. These data suggest that UPA is ineffective at preventing pregnancy if taken after ovulation, implying that UPA has negligible effect on postovulatory mechanisms related to establishment of pregnancy.

  • 6. Gómez-Elías M.D., Munuce M.J., Bahamondes L., Cuasnicú P.S., Cohen D.J.: In vitro and in vivo effects of ulipristal acetate on fertilization and early embryo development in mice. Hum Reprod 2016; 31: pp. 53-59.
  • 7. Levy D.P., Jager M., Kapp N., Abitbol J.L.: Ulipristal acetate for emergency contraception: post-marketing experience after use by more than 1 million women. Contraception 2014; 89: pp. 431-433.
  • 8. Glasier A.F., Cameron S.T., Fine P.M., Logan S.J., Casale W., Van Horn J., et. al.: Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized non-inferiority trial and meta-analysis. Lancet 2010; 375: pp. 555-562.
  • 9. Stratton P., Hartog B., Hajizadeh N., Piquion J., Sutherland D., Merino M., et. al.: Nieman LK. A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women. Hum Reprod 2000; 15: pp. 1092-1099.
  • 10. Noyes R.W., Hertig A.T., Rock J.: Dating the endometrial biopsy. Fertil Steril 1950; 1: pp. 3-17.
  • 11. Passaro M.D., Piquion J., Mullen N., Sutherland D., Zhai S., Figg W.D., et. al.: Luteal phase dose–response relationships of the antiprogestin CDB-2914 in normally cycling women. Hum Reprod 2003; 18: pp. 1820-1827.
  • 12. Stratton P., Levens E., Harto B., Piquion J., Wei Q., Merino M., et. al.: Endometrial effects of a single early-luteal dose of the selective progesterone receptor modulator CDB-2914. Fertil Steril 2010; 93: pp. 2035-2041.
  • 13. Foulk R.A., Zdravkovic T., Genbacev O., Prakobphol A.: Expression of L-selectin ligand MECA-79 as a predictive marker of human uterine receptivity. J Assisted Reprodutcion and Geneteics 2007; 24: pp. 316-321.
  • 14. Horne F.M., Blithe D.L.: Progesterone receptor modulators and the endometrium: changes and consequences. Hum Reprod Update 2007; 13: pp. 567-580.
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  • 16. Myers E.R., Silva S., Barnhart K., Groben P.A., Richardson M.S., Robboy S.L., et. al.: Interobserver and intraobserver variability in the histological dating of the endometrium in fertile and infertile women. Fertil Steril 2004; 82: pp. 1278-1282.
  • 17. Murray M.J., Meyer W.R., Zaino R.J., Lessey B.A., Novotny D.B., Ireland K., et. al.: A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril 2004; 81: pp. 1333-1343.
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  • 19. Lira-Albarrán S., Durand M., Larrea-Schiavon M.F., González L., Barrera D., Vega C., et. al.: Ulipristal acetate administration at mid-cycle changes gene expression profiling of endometrial biopsies taken during the receptive period of the human menstrual cycle. Mol Cell Endocrinol 2017; 447: pp. 1-11.
  • 20. Rosario G.X., Stewart C.L.: The multifaceted actions of leukaemia inhibitory factor in mediating uterine receptivity and embryo implantation. Am J Reprod Immunol 2016; 75: pp. 246-255.
  • 21. Uchida H., Maruyama T., Ohta K., Ono M., Arase T., Kagami M., et. al.: Histone deacetylase inhibitor-induced glycodelin enhances the initial step of implantation. Hum Reprod 2007; 22: pp. 2615-2622.
  • 22. Lira-Albarrán S., Durand M., Barrera D., Vega C., Becerra R.G., Díaz L., et. al.: A single preovulatory administration of ulipristal acetate affects the decidualization process of the human endometrium during the receptive period of the menstrual cycle. Mol Cell Endocrinol 2018; 476: pp. 70-78.
  • 23. Lessey B.A.: Assessment of endometrial receptivity. Fertil Steril 2011; 96: pp. 522-529.
  • 24. Berger C., Boggavarapu N.R., Menezes J., Lalitkumar P.G., Gemzell-Danielsson K.: Effects of ulipristal acetate on human embryo attachment and endometrial cell gene expression in an in vitro co-culture system. Hum Reprod 2015; 30: pp. 800-811.
  • 25. Lalitkumar P.G.L., Lalitkumar S., Meng C.X., Stavreus-Evers A., Hambiliki F., Bentin-Ley U., et. al.: Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model. Hum Reprod 2007; 11: pp. 3031-3037.
  • 26. Ortiz M.E., Ortiz R.E., Fuentes M.A., Parraguez V.H., Croxatto H.B.: Post-coital administration of levonorgestrel does not interfere with post-fertilization events in the new-world monkey Cebus apella. Hum Reprod 2004; 19: pp. 1352-1356.
  • 27. Vargas M.F., Tapia-Pizarro A.A., Henríquez S.P., Quezada M., Salvatierra A.M., Noe G., et. al.: Effect of single post-ovulatory administration of levonorgestrel on gene expression profile during the receptive period of the human endometrium. J Mol Endocrinol 2012; 48: pp. 25-36.
  • 28. Boggavarapua N.R., Bergera C., von Grothusena C., Menezesb J., Gemzell-Danielsson K., Lalitkumar P.G.L.: Effects of low doses of mifepristone on human embryo implantation process in a three-dimensional human endometrial in vitro co-culture system. Contraception 2016; 94: pp. 143-151.
  • 29. Li H.W.R., Li Y.X., Li T.T., Fan H., Ng E.H., Yeung W.S., et. al.: Effect of ulipristal acetate and mifepristone at emergency contraception dose on the embryo-endometrial attachment using an in vitro human trophoblastic spheroid and endometrial cell co-culture model. Hum Reprod 2017; 32: pp. 2414-2422.
  • 30. Li H.W.R., Lo S.S.T., Ng E.H.Y., Ho P.C.: Efficacy of ulipristal acetate for emergency contraception and its effect on the subsequent bleeding pattern when administered before or after ovulation. Hum Reprod 2016; 31: pp. 1200-1207.
  • 31. Trussell J., Ellertson C., Dorflinger L.: Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of intercourse: implications for mechanism of action. Contraception 2003; 67: pp. 167-171.
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3 hours ago, Boatswain2PA said:

This was sent to me from a source who wants to remain anonymous.  I have not been able to read the link yet.

"Drop this on them:  https://pubmed.ncbi.nlm.nih.gov/25698840/

I don't post on the forum anymore.  Too much bullshit and favoritism, with selective censors."

The article is from the Linacre Quarterly.

"The Linacre Quarterly is a peer-reviewed academic journal that was established in 1932. It is the official journal of the Catholic Medical Association and primarily focuses on the relationship between medicine and spirituality, and in particular on medical ethics."

And you talk about ACOG being biased.

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