Thread by @StupidRock

#Science time, nerds. 🤓👩‍🔬👨‍🔬

To understand if medical #abortion — aka chemical, at-home, self-managed abortions — are reversible, we need to know how they work; to know how medical abortion works, we need to understand a bit about how #pregnancy works.

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https://twitter.com/StupidRock/status/1338624147384131586

Citations at the end of the thread! All but 2 are free full access, all but 2 are journal articles (& 1 of those 2 is a textbook).

Progesterone (prog) is known as the “pregnancy hormone.” Until ~10 weeks post-fertilization, prog is produced by the woman’s corpus luteum...

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...(located in her ovary, a mass of cells formed after a follicle popped out an egg). After 10 weeks, the placenta (a shared/feto-maternal organ) actually takes over the production of prog.

Prog does a LOT for pregnancy.

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Probably the most common thing prog is known for is maintaining the uterine lining.

A drop in prog precedes menstruation, for example, and low prog can inhibit an embryo from ever implanting. The surface cells of the uterus have prog receptors (PRs).

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When prog is produced and binds to PRcs, this triggers the endometrium of the uterus to do It’s Thing and prepare for implantation and maintenance of the growth of the embryo/fetus.

A lesser-known but v. important role of prog is modulating the immune response of the mother!

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One way of doing this is for prog to bind to PRs on certain white blood cells. Once prog binds to PRs, the molecules can travel to the nucleus of the cell and interact with the DNA to modulate gene expression. This activity signals the immune system to produce less of...

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...certain cytokines (an assortment of different molecules associated with the immune system which affect cells). These types of cytokines could signal an immune response to the embryo/fetus; but the same process at the same time tells the cell to produce more of another...

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type of cytokine which won't do that crap, plus produce a specific protein which *also* helps regulate immune response of mom's body.

This is an overly simple explanation of 1 part of a very intricate dance at the cellular level between the embryo/fetus and mother’s bodies.

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Prog supplementation has been used for decades as a normal part of artificial reproductive technology to improve the chances of embryo implantation and continued gestation, with clearly beneficial results. It has also been used to treat women at risk .for preterm birth and...

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...those who have a history of miscarriage, with neutral or decidedly beneficial results based on the study considered.

Now here’s how a chemical abortion works: RU-486 — aka mifepristone, Mifeprex, Korlym — ALSO binds to PRs!

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Ru-486 is a chemical look-alike to prog (see the two drugbank citations at the end to look at the structures). So it tricks PRs, binds to them, BUT then the PRs can’t carry out their normal functions.

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So the PRs in the endometrium are no longer being signaled to maintain that uterine lining, and the mother’s immune response to the baby is no longer being modulated. The uterine lining will start to break down, which is what eventually kills the embryo or fetus via...

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...lack of oxygen and/or nutrients, which can’t be passed from mother to child when the mother and child are no longer connected.

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RU-486 has some other modes of action, like making the uterus sensitive to contraction-inducing prostaglandins (like mifepristone, the second part of a medical abortion).

BUT here’s the kicker:

RU-486 is a COMPETITIVE inhibitor of progesterone!

What does this mean?

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If you took an undergrad biochem class recently, you might remember learning about competitive, non-competitive, and uncompetitive inhibitors and binding affinities of inhibitors vs the intended/natural binding molecule. If you haven’t taken one recently:

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A competitive inhibitor binds to the same binding site on a receptor as the intended molecule & inhibits the action of the receptor when it does so.

The great thing about competitive inhibitors is that they can be OUT-competed by introducing more of the intended molecule.

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(this is how many drug treatments like penicillin work, for example)

I.e, if you flood PRs with enough prog, prog will outcompete RU-486 and take over binding to the PRs again — which re-starts or maintains what the body was already doing under prog’s influence originally.

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The relative binding affinity (comparatively, how well one molecule binds to a receptor compared to another molecule) of RU-886 and prog is pretty close in biochem terms, with RU-486 being about twice as good at binding to the PR than prog.

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This means it would be quite reasonable to expect to be able to introduce more progesterone in a sufficient amount to outcompete the available RU-486.

So does #AbortionPillReversal work? Yes.

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The chance of completing a healthy pregnancy is about 2-3 times as likely when administered progesterone after taking RU-486 (48-68% chance) than the upper bound of just not taking anything at all after ingesting RU-486 (25% chance or lower).

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The chance for reversal increases the quicker progesterone is started after taking RU-486 and the later in pregnancy a woman is.

SHOULD #AbortionPillReversal work, biochemically? Also yes.

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References below

References for prog role in pregnancy/fertility and prog supplementation for various reasons:
fertilitycenter.com/fertility_care…

journals.physiology.org/doi/full/10.11…

ncbi.nlm.nih.gov/pmc/articles/P…

ncbi.nlm.nih.gov/pmc/articles/P…

ncbi.nlm.nih.gov/pmc/articles/P…

ncbi.nlm.nih.gov/pmc/articles/P…

ncbi.nlm.nih.gov/pmc/articles/P…

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ncbi.nlm.nih.gov/pmc/articles/P…

obgyn.onlinelibrary.wiley.com/doi/pdf/10.111…

References for RU-486 info on modes of action and binding info for both drugs:

go.drugbank.com/drugs/DB00834

go.drugbank.com/drugs/DB00396

guidetopharmacology.org/GRAC/ObjectDis…

sciencedirect.com/science/articl… (behind a paywall)

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Penicillin as a competitive inhibitor:

chem.libretexts.org/Bookshelves/Or…

Reference for #AbortionPillReversal success rates:

pubmed.ncbi.nlm.nih.gov/30831017/ (behind a paywall, can still see final outcome numbers)

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