Making sense of transdermal HRT doses

While the gel hrts are proving very successful for some users, others are having puzzlingly disappointing results with them. There's a lot of individual difference in how well we each may take up any given transdermal medium, but in the case of gels, this doesn't seem quite in sync with what these same users may find with other transdermal media.

The one way that gels stand out from, say, creams or lotions, is that they dry on the skin rather than having the hrt, medium and all, absorbed into it. Product labels warn of enhanced risk for transferring gel-delivered hormones to others and for diminishing the delivered dose by washing too soon after application (where "too soon" is a much longer period than with other media).

The gels

It's also puzzling to users trying to calculate doses when they switch from one form to another of hrt just how the relatively large amounts of estrogen in the typically-recommended gel hrt doses should be compared to the amounts delivered by other hrt forms.

One of the members of our discussion list shared with us this excellent article that may shed some light on all of this: "Comparison of the transdermal delivery of estradiol from two gel formulations." According to this test, which compares two widely-sold gel hrts, the delivered dose of the hormone was only 13-20% of the amount applied.

All hrt deliveries involve some losses: that's one reason why we can't just convert from one hrt to another of a different route and go on using the same dose numbers. But in the case of gels, we need to recognize that there will be a big difference because such a small amount of the hormone actually gets into our bodies this way. And with such a low proportional delivery when used according to directions, it doesn't take much imagination to suspect that this could be further reduced by incorrect application.

Yes, that's a lot of loss. Where does it go? Well, onto our partners and kids, if we're not careful. Onto our clothing and towels and bed linens, I'm sure. Ultimately, down the drains of our showers and washing machines, into our sewers and septic systems, thus contributing to the contamination of water supplies that today test in community after community as having elevated estrogen contents and perhaps contributing to the cancer and other hormone risks of an entire population. It's not our place to advocate for ethical issues here, but this might be a point that users would want to consider when they make their own choices.

Other transdermals

As we said above, each hrt, even within the family of transdermals, has its own delivery profile. That includes things like how the uptake "feels" to us and how efficiently it moves the hormones it contains into our systems. We've seen way too many users just slam themselves with excessive doses when they thought that because they needed X mg of dose in one transdermal hrt, they needed to multiply normal doses of another hrt to get that same number.

That's not how it works.

We can get a better sense of dose equivalency from the "usual starting dose" figure that's part of the basic prescribing information with any hrt. That's the dose that incorporates enough to make up for losses in delivery and still provides enough to make up "usual" coverage in a user's system.

Yes, this is confusing. One of our discussion list members assembled this very handy chart comparing dose to delivered amounts in transdermal products available in the US and the UK. It doesn't cover every hrt or all the generics, but it does give us a great overview of how much variation there is in all of this.

So how do I use this information?

Basically, it reinforces the premise that we really can't do an absolute conversion from any one hrt to any other hrt. But it does help us feel more comfortable letting go of dose numbers as even a rough conversion factor and switching our attention to more useful figures.

What we can ask, in moving from one hrt to another, is how we felt on what dose of our original hrt. If we felt sort of okay on, say, the usual starting dose of our old hrt, then we might want to start the new hrt at whatever is pegged as the usual starting dose for that one. Similarly if we were one standardly sold dose up or down from the usual starter of our old hrt (or we would have preferred to have been), we might look to that many iterations off of usual starting for the new one. It's a really rough and imprecise system and no, the manufacturers aren't going to provide us with anything better because their profit lies in holding us captive to their brand, not in facilitating our moving to someone else's.

We can also use our understanding of this to help explain why we may feel really different when we switch brands. We typically see this when we're having problems with one brand and our doctor switches us to another and whammo, we're feeling as though our hrt has just evaporated. Many doctors may not be up to date with the trend that some hrts now come out in ultra low doses meant for those in natural menopause who just want a tiny hormone boost for its value in combating osteoporosis. Those doses aren't typically enough for most users in surgical meno, so even swapping to the "usual starting dose" of the ultra-low hrts is a huge dose cut. Again, when we look at the figures for what is being delivered, we can get a sense that we've actually had a big cut in what our bodies have to work with. So in this case, we're not crazy: we actually aren't taking anywhere near the same thing and we need to take this fact back to our doctors to use in troubleshooting our correct dose.

Obviously, dose amount and delivery amount aren't the only factors in working with the behavior of different transdermal hrts, but they are an important factor to understand when we are troubleshooting.

FDA approves two hrts: Endometrin and Evamist

The FDA has given new drug approval to two prescription products that might be useful to our readership as hrts.

Endometrin

Endometrin is a 100 mg bioidentical progesterone vaginal "insert" described further as a "white to off-white oblong-shaped tablet" to be administered with a plastic applicator. Inactive Ingredients: lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium laurel sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide.

The label indication is for fertility support, but, like Prochieve (ex-Crinone), the vaginal gel, it can presumably be used for other progesterone needs as well even though the limited data on the package insert does not discuss any use or data other than the fertility support testing done. The advantages of vaginal delivery of progesterone are mainly of interest to those taking largish doses, out of scale with their level of need, to accomplish therapeutic, rather than hormone balancing, objectives. These would include things like treating endometriosis as well as protecting a uterus from excessive estrogen stimulation by hrt. The advantage is that more of the hormone is delivered into local circulation and systemic effects of the dose are minimized.

The 100 mg provided dose is hefty, but may not be out of line with what some of us are using. Since the tablet is to be stored at normal room temp, it probably is a typical firm chalky pill. Still, it should be possible to divide it with care if some dose customization is desired.

This is an approval by the US FDA; we're not aware of it being for sale in other countries, but if anyone knows differently, please let us know.

Evamist

Evamist is a transdermal spray delivery of bioidentical estradiol approved for use in menopause (that is, licensed only for hot flashes). One spray delivers 90 mcL which contains 1.53 mg estradiol; starting dose is one spray daily to the forearm but the dose may "increase to two or three sprays daily to forearm based upon clinical response" to adjacent, non-overlapping areas. "Sprays should be allowed to dry for approximately 2 minutes and the site should not be washed for 30 minutes." Inactive ingredients: octisalate (a common active ingredient in some sunscreens used to enhance skin penetration), alcohol (to dissolve the drug).

It is important to note that although the dose itself contains 1.53 mg of estradiol, that is not the amount actually delivered systemically. That delivered amount is 0.021 mg, making one spray roughly equivalent to the lowest range of patch doses and stepping up roughly at the same dose intervals as we add additional sprays. Many doctors and users don't notice this difference and mistakenly assume from the lack of response to the nominal 1.53 mg dose that their dose needs are somehow much higher than typical. In fact, their response is to the 0.021 mg delivered dose and that's the figure we need to work with in considering equivalency to other hrts.

"Application of Evamist to other skin surfaces has not been adequately studied." That means, of course, not that it won't work, but that the manufacturer didn't pay for that extra research as part of their licensing application. There is no reason to suspect that the usual other safe areas might not work, although each area's absorption might vary according to the tissue and circulation present in each. The forearm typically has relatively low fat overlay and good, close-to-surface blood vessel presence, so this would provide for a faster uptake and less tissue storage than, say, the butt or belly or thighs.

The precautionary text in the package insert is pretty much standard for estrogen. Of interest in the adverse reactions table is that while nausea was sharply lower than placebo at low doses, it rose with higher doses--as one would expect in sensitive individuals using an hrt with a half-hour uptake curve. Note also that nasopharyngitis (those puzzling sinus/ear symptoms) are also present with it, especially (we don't know why) with the low dose--although that might well represent the beginning of use and the higher doses being used in those who have accommodated to estrogen use. Headaches are also seen at a higher level in the users as opposed to the control group, and we suspect that these are also the uptake-sensitive individuals. That doesn't mean, however, that this would not work for them--this was a short trial (70 days) and it could be that once stabilization occurs and normal body caching mechanisms are in place, this is less of a factor. That's no compelling reason to rule it out without trying it if it otherwise is an attractive choice.

Because the dose is delivered by a metered spray pump, dose customization would be difficult beyond the number of sprays per day. Nonetheless, a creative individual could possibly cover some proportion of the area to be sprayed with a shield of some kind--although that's not likely to be wholly accurate (more than you'd think, though, since the sprayer is actually a bell-shaped template that fits snug against the skin to control the size of the area applied to). Trying to bypass the pump and just work with the liquid would also be tricky since the amount of spray volume would be roughly 0.135 ml and that's a very tiny amount to measure out.

One of our discussion group members has shared with us how they managed to manipulate the dose and has given us permission to share their discovery:

I did figure out how to reduce the [dose amount] from the evamist pump. The circular dispenser comes with a cover. I took an old cover or cap and cut it in half. Worked great! The "half" cover snaps right on like the full cover. There is a felt like material inside the cover and it's not securely attached so it does become loose when cut.  I'm going to take a tiny drop of glue and attach it to the inside of the cover. It needs to be there to catch and absorb the excess spray so that it doesn't drip. It might be possible to do a smaller cut or a larger cut with the cover. 

The sprays are supposed to be placed side by side but not overlapping. When using the "half cover" make sure the "open half" is placed next to the full spray or else there will be a separation between sprays. Maybe not that important but it more accurately follows the manufacturer's instructions.

No transfer of the estradiol to a partner was measured one hour after dose application, so this form is seemingly more fully absorbed into the skin than gels or lotions are. "When sunscreen is applied approximately one hour after application of Evamist, estradiol absorption was decreased by 11%. When sunscreen is applied approximately one hour before the application of Evamist, no significant change in estradiol absorption was observed." The text does not distinguish between oil-based and non-oily sunscreens, but as with all transdermal hrt use, the oils used on the skin may make a difference depending upon whether they are digestible or not. Using non-oily sunscreens would probably have the lowest impact on hrt dose dynamics.

So this gives us one more retail transdermal estrogen hrt option, although like all of the other retail hrts, it provides only estradiol, not the other estrogen forms that can be obtained through compounded hrts. That may or may not make any difference for a particular individual. Estradiol is widely-enough tolerated that it is not necessary for most of us to begin with anything else unless we have a particular philosophical preference for doing so or have prior estrogen experience to suggest a need for the less active estrogens. It is somewhat less customizable in dose than the other retail transdermal estradiols, but then, dose customization is not something that is encouraged by the FDA licensure system (because approvals are absolutely specific to the doses tested) and so manufacturers generally design packaging/delivery that may thwart dose variability and customization.

NEWS: testosterone alone is not enough to provide for libido

"Testosterone cream fails as sex drive booster" is the title of a Reuters press release that caught our eye. A copy of the full study article is available from the Journal of the National Cancer Institute, which published it.

The study is a small one and deals with women who are not taking HRT. They found that testosterone cream in a dose of 10mg (!) daily for four weeks did not restore libido despite rising serum levels of the hormone. The press release goes on to say:

It's likely, Barton and her colleagues conclude, that a woman must have adequate levels of estrogen in order for testosterone to be an effective treatment for low libido.

In a related discussion in the editorial section of the Journal of the National Cancer Institute, the authors (of the editorial) note that some 31% of the study participants were taking an aromatase inhibitor, which might also have an effect on total hormone synthesis. While 72% of the participants had an "intact" ovary, ovarian function was not, seemingly, determined. Of sudden menopause, they go on to say,

chemotherapy-induced menopause, which is more abrupt than natural menopause and can have more profound physiologic and psychologic manifestations

This article also reports the results in interesting detail:

The negative results from this study are clearly stated for the primary endpoint of libido (desire/interest) as well as the secondary endpoints of mood, vitality, sexual pleasure, and total sexual functioning. The authors report no statistically significant improvement with treatment compared with placebo for any of these endpoints. Biologic measures that paralleled the questionnaire data from this study revealed statistically significant increases in bioavailable, free, and total testosterone in the treated group, and no changes in serum estrogen, sex hormone–binding globulin, or serum aspartate aminotransferase. These findings suggest that transdermal treatment with 2% testosterone did lead to measurable changes in testosterone levels and that in this short-term study there were no adverse effects on estrogen levels or liver function tests. However, between baseline and 8 weeks of follow-up, both groups showed improvement in almost all the outcome measures, although not differentially by treatment condition, suggesting that there was a large placebo effect in this study sample. Such an effect is consistent with a developing body of neuroscience research on the placebo response, demonstrating direct actions of the placebo on the brain and then subsequent effects on the body such as alleviation of pain or other symptoms.

The authors go on to acknowledge the importance of estrogen in libido, both with respect to vaginal atrophy and in supporting other sensations related to desire. This is exactly the position suggested by the Endocrinologists' Society guidelines (free signup required to read), which also state that estrogen must be brought up to normative levels as the fundamental first step before testosterone can even be reliably evaluated.

Does this conflict with the assertion that in estrogen deficiency testosterone is likely to just be used as an estrogen source? No, that data is fairly clear, as is the risk for women with estrogen-sensitive cancers in taking testosterone. We suspect that in this case the testosterone was simply inadequate to provide that foundation level of estrogen, and so the overall hormone need situation was not especially improved by its use. It's also unclear the extent to which the hormonal therapies for their cancers were affecting both the ability to produce and to synthesize estrogen from other hormones.

What's the takeaway for those of us who are not involved with cancer? I think that the lesson here is clear for all of us in common: testosterone is not a simple remedy for libido loss. This adds to the body of evidence that points to estrogen as the foundation of libido, and that, in practical terms, we must address this deficiency before we can look to adding testosterone as a magic bandaid, however appealing that this may look in simplistic terms.

And, as the editors and authors cited here note, testosterone's risks in women remain very poorly defined. The fact that there is not a lot of information out there pertaining to testosterone's risks for us does not mean that no risks exist, although for those who get their health guidance from CNN, that may certainly appear to be the case. The list of "side effects" of licensed testosterone products does not constitute research into total risks, nor do symptom lists constitute an evaluation of the underlying processes. We simply do not have strong, reliable, large-population, controlled research into how testosterone functions in women and what risks go along with its supplementation.

Does all of this mean we are against all use of testosterone? Not at all. But we are, as we are with any hormone or HRT, strongly against use based on simplistic binary criteria with a poor acknowledgment of risks: wishful thinking is not realistically safe menopausal strategy, and in such highly-loaded stakes as sexual function, we are especially vulnerable to just that danger.

Based on our present, limited state of knowledge, it does make sense that estrogen needs are what we should address as our foundation, and that only after we have seen effective estrogen support to be achieved can we begin to explore other forms of support, one of which may be testosterone. We don't feel that testosterone is "the answer" to libido, although it may be part of the complex factors that contribute to it. And we certainly don't feel that testosterone is "safe" any more than we feel that any hormone, powerful compounds that they are by their very nature, is "safe."