There is, of course, one vaginal-delivery systemic estrogen hrt on the market already, Femring. But we're also seeing some individuals report exploring the use of Estrace and its generics (micronized estradiol) vaginally for systemic support. And that raises some distinct concerns.
Vaginal micronized estradiol: will it work?
First of all, yes, absorption through vaginal tissues will function as a delivery route for this hrt. Oral mucosa is very similar to vaginal and it is indeed permeable to this molecular form of estrogen. In fact, it's been quite some years now since we first heard of using a tiny bit of the dust leftover from cutting tabs for transbuccal or oral use for local vaginal supplementation. We had some concerns initially that either the colorant or the base might prove problematic since neither are designed for the vaginal environment, but that has not been the case for those who've shared their experiences with us. We've also run this past a few doctors who have said there doesn't seem to be any obvious peril beyond the issue of making sure the dose is appropriate. So that seems to be both effective and reasonable as a means of local supplementation. But that's not the same thing as using this delivery for systemic support.
Risks: concentration in pelvic circulation
Our greatest concern with using this route for systemic vaginal dosing, however, is where that estrogen goes immediately after it is absorbed.
With transbuccal use, many users see distinct local effects according to where in their mouths the tablet is placed. Those seem primarily to do with fluid retention (such as sinus stuffiness, ear fullness or transient headache) and we have speculated that they represent higher local concentrations in the part of the circulation to which they are initially delivered, before they are well-diluted. Most of those reporting this effect have had success in switching to other locations in the mouth where this is less problematic, although the non-problematic location varies (of course it does) from individual to individual.
Looking at that same aspect in terms of vaginal delivery, then, we have a concentration of estradiol—which is the active form of estrogen—delivered to local pelvic circulation. We know from research done with vaginal progesterone that this kind of concentration in the pelvic area does happen with vaginal delivery of that hormone supplement and there is no reason at all to expect that estradiol could escape a similar distribution pattern.
Now, when that happens with progesterone, that represents a desirable situation in terms of delivering a therapeutic concentration of that hormone to pelvic organs without causing a corresponding systemic concentration—and heightened systemic effects. But with estrogen, there's no real reason that this concentration would be desirable and in many situations, we're quite concerned that it isn't. Anyone with endometriosis, for example, would hardly want higher estrogen concentrations flowing directly to their endo implants. Anyone with a risk of ovarian cancer retains that risk even when their ovaries are removed because there is a (low but present) risk that before oophorectomy, micro-tumors may have escaped their ovaries to later be stimulated by that higher level of estrogen in the circulation that feeds them. This is recognized in the specific warnings for current vaginal systemic hrt, that caution high risk users about precisely this.
We know from users of the systemic vaginal ring that some find this route of supplementation to be highly uncomfortable, citing symptoms of pelvic bloating or congestion as well as stimulation of irritable bowel syndrome or bowel cramping. There is also a mixed body of evidence suggesting that higher levels of estrogen may add to incontinence. So not only do we have the progesterone model to shape our expectations but we have experience with vaginal delivery and pelvic symptoms to suggest that it most certainly does happen and we have FDA concurrence that this represents an undesirable level of risk for at least some users.
It is worth noting that Femring, the vaginally-delivered systemic hrt, uses a form of estradiol that, although human-identical, is inactive until it has been further processed in the bloodstream. This means that it is well on its way to being diluted and distributed before it becomes fully active as estrogen. It seems likely that this is deliberately done to reduce estradiol activity exposure at systemic levels to those pelvic tissues. In other words, there may be significant negative concerns with vaginal delivery of systemic estrogen that led the pharmaceutical companies to put additional funding into working around that problem rather than, more economically, just repurposing an existing product they already had on the shelf. While we may not know what led them to do so, the simple fact that they spent money on this raises the warning flag that it was probably not done without substantive reason.
Risks: estrogen activity and vaginal tissue health
Were an individual to elect to try vaginal estradiol systemic hrt notwithstanding the above risks, we would also think that a regular, detailed and careful exam of vaginal tissues by a knowledgeable practioner would be important. While the low-dose vaginal hrts are documented to have a fairly light effect on the tissues they directly contact, all that systemic-dose estrogen going through a relatively small location (even though the tab breaks up quickly, it's still not going to be distributed over a wide area of mucosa in the fairly static vagina) may have disturbing effects upon the mucosal cells in that area.
This is a concern raised by some doctors when users discuss transbuccal use, based upon similar issues seen with some sublingual and nasal drugs. Those using this route need to be careful to switch locations around frequently, visually check their oral mucosa regularly, and also ask their dentists and oral hygienists to do so as a backup. We see no reason why similar precautions with vaginal use would not be a good idea (only, of course, probably not asking your dentist to be the one do it) to make sure that we are not stimulating some sort of cellular changes that could become problematic. Remember: the reason why estrogen is carcinogenic is that it fosters growth of tumors, and that's not something we want going on out of sight in our vaginas.
Would this work with any of the oral estrones?
That's a good thought that came from our discussion of vaginal systemics on our discussion forums. We don't really know, but it seems as though since there was an Ogen vaginal cream made for local use, the oral estrones Ogen or Ortho-Est would seem to be usable transbuccally or vaginally since they contain the same compounds.
That said, many of the same concerns with respect to vaginal systemic dosing would still apply. Although estrone is an inactive form of estrogen, the conversion of estrone to estradiol occurs in cells throughout the body. A higher-than-normal local concentration of estrone might well still result in higher-than-desirable estradiol exposure to vaginal and pelvic tissues. We certainly don't see any reason why switching out estrone for estradiol would moderate risk adequately that those with specific risk factors such as endo or ovarian cancer could be confident that this would safer for them, however much the systemic impact might be gentler than all-estradiol dosing.
So should we use oral hrts vaginally or not?
We have really mixed feelings about this whole premise. That it would work to deliver estrogen to our systems, there is little doubt. It is likely that in reaching the circulation through pelvic rather than head/upper body dilution, the specific local effects that are problematic for some women with transbuccal use might be avoided.
We can't, however, see that it in any way alters the way the dose is processed by the body other than that initial concentrated absorption uptick, so the premise that it somehow is delivered more evenly than transbuccal is likely a subjective impression that is not supported by physiology. It may be different from other transdermal (general body skin) deliveries, just as transbuccal is, because it represents a different uptake dynamic and the skin/fat reservoir and transmission effects are taken out of the mix. Like the transdermals, however, it also represents a risk of transfer to a partner than is unquantifed but certainly real.
We've taken up elsewhere the issues of whether not estradiol needs to be dosed multiple times per day and whether "even" is ever a state that can be achieved (spoiler: no, it's a myth), so we won't reference those concerns here other than to say that there is nothing in pelvic delivery that would lead us to feel they are not applicable here as well. Anyone whose body is not capable of using a daily dose via this route, as with any other, is not utilizing that particular hrt well. Whether or not other hrts would better suit them is the issue here, not just the route and timing; multiple-dose dosing is a stopgap measure to try to force a fit with a deficient hrt, not a good or sustainable strategy in itself (although it's true that in some instances where trying other things is truly not feasible, stopgaps may be the best thing we have within our reach). The ability to divide a vaginal dose into micro-doses given at extremely short intervals is thus not a compelling argument that in any way offsets the risks, let alone makes this route somehow unique.
So the bottom line on this is that there's just no reason to be really comfortable with the risks that this concentration provides in this location. That doesn't mean it mightn't be the more practical option for some women, but it would require special precautions that make it nothing to be taken lightly. One of the dangers of discussion forums that focus on support rather than information is that women can advocate for use of a particular hrt strategy without any corresponding exploration—or even awareness—of the risks it poses.
We do think this notional hrt use is worthy of exploration, but that exploration should be done knowledgeably and with great care to monitor for negative outcomes. Given the widespread lack of understanding of hrt and hormone effects, though, we're afraid that users will be injured by and later regret decisions made without fully understanding those risks. Individuals with hormonal concerns may distrust their doctors because that relationship is so formulaic, paternalistic, and illness-based, ill-suiting their menopausal health needs. Yet when they engage in risks without that backup of medically sophisticated knowledge, they've lost an important safety net. Maybe it looks as though we're being too conservative in this case, but with things we can't get back from without great cost, yeah, conservative does have positive benefits.
But then what about compounded hrt to be used this way?
Are compounded vaginal estrogen hrts being prepared for systemic use? What are compounders doing about these issues? We're not seeing direct-to-consumer advertising of this type of hrt, so we don't really know if this market niche currently exists and we haven't yet encountered anyone who does.
Because there is no substantive difference between retail human-identical and compounded bioidentical hrts in terms of this risk situation, our concerns would definitely extend to those hrts as well. While doctors in theory vet the prescriptions suggested by compounders, in practice many of them tend to just pass them on as suggested by a fully qualified professional and happily pocket their share of the business income so generated. So there's a questionable safety net right there.
In fact, if they are doing so, this would be exactly where we tend to think that the FDA has a reasonable ground to be critical of compounding. This would be a major departure from what is known and tested and generalizable from other tested and licensed retail hrts. This is where their current practice model might indeed overstep their training and licensure and, of course, constitute the legal vulnerability that is being exploited by the pharmaceutical companies in response to what is actually a perceived marketing threat rather than the nominal concern for patient safety in which it is couched.
So we're going to hand this part of the question back to you. What do compounding pharmacists you are working with have to say about direct systemic vaginal estradiol hrts? And estrone used that way? Are they making and selling it? What precautionary screenings are they doing or what counseling are they doing on risks specific to this delivery? We'd be very interested to know what the compounders' take on this is. If you have any information, please do share the results of your inquiry with us.
This is an idea we need to explore just because there are indeed individuals out there claiming to be using this route and promoting it on discussion forums. The more concrete the information we have, the more useful it becomes to us, whether it's to give us the go-ahead to experiment more freely or to convince us that it's really not such a good idea after all. We're not at all opposed to exploring and pushing the envelope in search of alternative ways to use the available hrts, but we're always going to be taking a firm hard look at the risks along the way.
