Tuesday, 22 April 2014

Clarity on gel HRTs

Last week I posted a cut-and-paste copy of an email update I received from A Survivor's Guide to Surgical Menopause, to which I subscribe. Today I received yet another interesting update which I thought some of you may find useful too...


Fair warning: The material in this article is long and dense. It's important stuff, but if you really just want to gloss over the nitty-gritties, then skip down to the final summary.



Troubleshooting gel HRTs

The newest hrt delivery on the market is the gel, and because it's being heavily promoted by the drug reps, it's the current chic in hrt. Lots of women are being given gels as their first hrt. Lots of women are being given gels when they've had difficulties with other hrts. But this hrt isn't entirely straightforward to use and our experience with other hrt forms may not prepare us for using this one properly.

We're certainly seeing more women coming to the forums lately complaining of problems with gels, but it's hard to tell from the women who are online talking about problems just how widespread a problem is: the women without problems aren't talking about it and are invisible to us. Still, it feels as though a disproportional number of new questions about poor hrt fit are coming from women who are trying to get comfortable on gels. In part, that may just be that we don't yet know how to use them most effectively because we don't know all of the little tweaks that, say, make patches work considerably better. We're going to take a look here at what we do know and see what guidance we can develop.

How gels deliver

A gel hrt is different to a cream in that while a cream is absorbed through the skin and into the tissues below it, where fat forms a buffer to pace its delivery, a gel dries on the skin and the drying and the skin itself form the only buffer. This means that the gel sits either in the top layer of the skin or is in circulation; there is no other location where it pauses in between.

There is some discrepancy, though, as to exactly the extent to which what is on the skin remains part of our reservoir of hormones. On the one hand, in Pharmacology of Estrogens and Progestogens:

The application of a hydro-alcoholic gel containing estradiol results in a rapid penetration of the estrogens into the stratum corneum; this stops after drying of the gel on the skin. As the absorption is proportional to the surface of application, deviations from the instructions may cause variations in the estrogen level and clinical efficacy. About 10% of the dose is absorbed by the skin during the 2 min until drying. The estradiol is stored in the stratum corneum and permeates through the epidermis into the dermal capillaries according to the concentration gradient between the stratum corneum and blood. This diffusion lasts for 2-14 h. The two available gel preparations differ in their concentration and mode of application.

On the other hand, in the Divigel package info, we have:

Washing the application site with soap and water 1 hour after application removed all detectable amounts of estradiol from the surface of the skin, and resulted in a 30 to 38 percent decrease in the mean total 24-hour exposure to estradiol.


The skin is made up of a number of layers. The stratum corneum is the top layer, just under the collection of dead cells and rubbish that make up the actual surface that we can touch. During the drying time, the dose we'll actually have available to us migrates into the stratum corneum. This creates the dose reservoir, from which the estradiol is then diffused into our systems over the next 2-14 hours, safe from mechanical removal. But, and this is a critical "but," it seems it's not safe from external influence entirely.

On the one hand, once the gel has dried, a process our first source says takes 2 minutes, we're to believe we've got a done deal, so to speak, and the working portion of the applied dose is ours to use. 

But we know from the second source that washing even an hour later removes the remaining unused/unabsorbed-into-stratum-corneum portion of the dose and although we'd expect any effect of that to be insignificant based upon the first reference, we see in the second that it's not as protected as we would infer; washing within an hour is said to reduce the dose delivered by 30-38%. 

So that portion of dried gel that rests atop the skin, above the stratum corneum, is in some way still an active component of the daily hormone dose. And this means that we do in effect have a dual reservoir here:

  1. The amount of hormone that penetrated to the stratum corneum, which, if the amount on the skin is undisturbed, provides for the full daily dose release and uptake by circulation over 2-14 hours, and
  2. The dried amount of hormone perched on the outermost layer of skin, the premature removal of which will reduce ultimate delivered systemic dose by 30-38%.

Why are we going into this in such detail? In part, successful use of this hrt and the precautions we must practice with it depend upon our understanding of its vulnerability to outside influence and losses. In effect, this hrt is like a patch without the backing, and it's not going to perform well for us unless we undertake its protection properly.

Before we leave the delivery issue, we do want to say a couple things about how this particular form of delivery fits in the overall spectrum of different effects upon our bodies. This is a transdermal delivery form, so it will work best for those women who have skin permeable to estradiol. All four gels currently on the market deliver human-identical estradiol, so comfort with all-estradiol hrt defines another subgroup of women for whom this hrt will work better (or worse, in the opposite case) than some others. 

But because of its unique on/in skin reservoir, the uptake from a gel could be somewhat faster than with creams, such that it's probably more comparable to a somewhat slower version of a transbuccal dose, with more of it entering the body initially but, with gels, a small amount still migrating through as the day goes on. We should therefore think of a gel as a daily-dosed delivery, not a trickle-dosed delivery like a patch, even though the end time for the gel delivery is sort of open-ended. And like all daily-dosed hrts, we should take this one in the morning, in a single dose, to best fit with our systemic circadian rhythms. 


Why this delivery can be problematic for us


One of the most important aspects to understand about gels is that they have a huge amount of wastage built into them. We'll look at the dose numbers in a bit; right now, we want to focus on the mechanics.

First, let's take a look at the use instructions for the four major gels, two from the US and two from the UK. US brands are required to label with some information that is not on the European labels, and yet this can be helpful in understanding how to use gels consistently. All of this information is direct quotes from the product sheets unless it is (in parentheses like this), in which case it is our comment.

Sandrena Gel:

The Sandrena dose is applied once daily on the skin of the lower trunk of the right or left thigh, on alternate days. The application surface should be 1-2 times the size of a hand. Application of Sandrena on area of 200-400 cm2 (size of one to two hands) does not affect the amount of estradiol absorbed. However, if Sandrena is applied to larger area absorption decreases significantly. To some extent, however, the estradiol is stored in the subcutaneous tissue from where it is released gradually into circulation. (Directions note not to wash for one hour after application, but no quantified details on loss are provided.) Do not store above 25°C.
Oestrogel:
The correct dose of gel should be dispensed and applied to clean, dry, intact areas of skin e.g. on the arms and shoulders, or inner thighs. The area of application should be at least 750 cm2. One measure from the dispenser, or half the prescribed dose, should be applied to each arm/shoulder (or thigh). (Directions note not to wash for one hour after application, but no quantified details on loss are provided.) Do not store above 25°C.
EstroGel:
The gel is applied over a large area (750 cm2) of the skin in a thin layer. The recommended area of application is the arm, from wrist to shoulder. Site washing 1 hour after the application resulted in a 22% mean decrease in average 24-hour serum concentrations of estradiol. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
And from the patient instructions: "To get the best effect, wait at least 2 hours before showering/swimming to allow the drug to be absorbed through the skin."

Divigel:

The application surface area should be about 5 by 7 inches (approximately the size of two palm prints). Washing the application site with soap and water 1 hour after application resulted in a 30 to 38 percent decrease in the mean total 24-hour exposure to estradiol. Store Divigel packets at 20 to 25°C (68 to 77°F). Excursions permitted to 15 to 30°C (59 to 86°F).
The washing exclusion is pretty important because that tells us how the reservoir can be reduced by not taking the correct care of the application site. In terms of the application, the Euro labels just give the hour-without-washing caution without quantifying the problem. In the US data, we see how much difference it can make: loss of a quarter to a third of our intended dose. And we should be clear that this isn't just about deliberate showering: going out into heavy rain, swimming, getting heavily splashed while washing the dog, or even just sweating heavily all can carry the same risk of removing our dried gel reservoir prematurely.

Further, some women have reported that washing even 5-6 hours after application has resulted in hormonal symptoms that seem to indicate dose delivery alteration. This doesn't really surprise us: the subject pools for drug license applications are very small and the results very tightly groomed to present a cohesive picture of product efficacy. We in surgical menopause are a small portion of the product market and not always a typical one, and this could be one place where our more complete reliance upon our hrts is going to show up. 

So while that first hour  is the major uptake time, there is still the "long tail" of uptake from the skin that seemingly can be altered by losses later in the day. Or, now that we think about it, simply re-wetting that pool of estrogen sitting on the skin, perhaps allowing more of it rather than less to be absorbed. We're not sure, as well, about the dried gel's solubility in sweat as opposed to alcohol (which is the major vehicle in the gel), but we know that sweating opens pores and allows enhanced uptake of a lot of things applied to the skin, so we think we'd be safer to assume that at least some uptake is changed by sweating.

The other area where the US labels hold more information is in the storage criteria. They all recommend the same "room temperature" holding, but that maximum may well be exceeded in an un-airconditioned home in the summer. The additional information of "excursions," which simply means the extremes to which storage can go before the substance is definitely affected, is especially useful. If damage to the hrt begins to occur at temperatures in excess of 86
°F / 30°C, then leaving them sitting in our car on the way home from the pharmacy while we shop or storing them in an un-airconditioned home during the summer could in fact exceed these limits. We should probably also question temperature effects when hrts are delivered by mail to a home postal box, carried around by a postal courier and then sitting in a hot box on the side of a house or out on the street. For women who do fine with a gel all winter and then in the summer it suddenly "stops working" for them, this is a possible explanation of why that might happen and offers a focus for troubleshooting efforts.

Now, it's important to keep in mind that the dose application directions vary according to the strength of the gel, so they are not interchangeable (although the fact that one goes on the arms and one the legs is not an absolute for each brand). In fact, there are two strengths/methods of dispensing of gels, one of each available in each country. There's more on the whole dose strength issue below, but what is critical about this, before we leave this section, is that the delivered dose of the hormone is only 13-20% of the amount applied. So there's a very large element of wastage built into the dose already. If we have thermal degradation of the product or excessive losses due to sweating, then, we'll be making a relatively notable incremental change in our delivered dose.

This whole issue of losses is probably a significant factor, then, in the uneven and seemingly random results some women are having with this hrt. Even the patch is pretty binary: stuck down or not. But other hrts and products haven't prepared us for this more vulnerable delivery, and so it may not occur to women (and even if they read the instructions it may not be clear) that it's not enough just to apply a gel; we also have to treat it carefully in transporting and storing it as well as once it's on our bodies. And that is fairly different to our experience with other hrts.


Why this delivery is problematic for others


So far we've been focused on the women using gels. But if gels are as easy to lose from our skin as they seem, that also raises the specter of transferring them to others around us: family, pets, and even strangers. That's not an idle fear. Let's see what the product information says about this:

Sandrena: nothing


Oestrogel: 

The gel should be applied by the patient herself, not by anyone else, and skin contact, particularly with a male partner, should be avoided for one hour after application."
 EstroGel:
The effect of estradiol transfer was evaluated in 24 healthy postmenopausal women who topically applied 1.25 g of EstroGel once daily on the posterior surface of 1 arm from wrist to shoulder for a period of 14 consecutive days. On each day, 1 hour after gel application, a cohort of 24 non-dosed healthy postmenopausal females directly contacted the dosed cohort at the site of gel application for 15 minutes. No change in endogenous mean serum concentrations of estradiol was observed in the non-dosed cohort after direct skin-to-skin contact with subjects administered EstroGel.
That above is in the clinical pharmacology section of product sheet; the patient instructions say just 
Cover the application site with clothing (such as a long-sleeve shirt) to prevent others from touching the application area and being exposed to the drug. Wait at least 1 to 2 hours (depending on your brand) before allowing others to touch the skin where the medication was applied. If someone accidentally touches the gel (or the application area within 1 to 2 hours), have them wash the area of contact on their body with soap and water as soon as possible.
Divigel:
As with most topical products, there is a potential for estradiol transfer following physical contact with Divigel® application sites. The effect of estradiol transfer was evaluated in healthy postmenopausal women who topically applied 1.0 g of Divigel® (single dose) on one thigh. One and 8 hours after gel application, they engaged in direct thigh- to- arm contact with a partner for 15 minutes. While some elevation of estradiol levels over baseline was seen in the male subjects, the degree of transferability in this study was inconclusive." and "The application site should not be washed within 1 hour after applying Divigel®.
This sounds to us as though there's a transfer risk that lasts at least as long as the time before we can wash the area, and that washing the area and covering it with clothing are the only remedies offered by the manufacturers. But we know from the information we looked at near the top of this discussion that washing also reduces the estrogen delivered. So we have to give up a portion of our dose, then, to protect our pets and families. That doesn't mean it's impossible to reconcile the two needs, but it does contribute to making use of this hrt less intuitive.

But in fact we're not sure that it's even this simple. What happens to the estrogen that gets on that long sleeve and then goes into the laundry? Does it get redistributed through our family's clothing? How about the towels we used when we washed? The notion that having a sleeve over it keeps the estrogen from passing along seems overly simplistic, and that really we can consider this a temporary buffer but not a definitive capture and disposal. Besides which, wearing a sleeve over it in the summer or when our job attire calls for something different seems like more of a limitation than other hrts require, not to mention the whole issue of what one does if, say, they work out daily by swimming laps in a public pool.

Beyond that, even, we have a broader environmental and social concern. If we're going to be washing this not insignificant portion of our dose down the drain every day, that dose is going into municipal wastewater treatment facilities or into the ground, from both of which locations it will migrate into water supplies. Neither wastewater nor drinking water treatments require removal of estrogens (along with lots of other drugs that are flushed for disposal or peed out every day). So this puts those estrogens into the water used by animals and other people, exactly what we find when we examine the environment for xenoestrogens that have been linked to higher rates of hormone-exposure disorders and earlier sexual maturing. We're not going to take a stand here about the ethics of this because that's not the focus of this site. We do, however, feel that it's only responsible that we point this out to women and ask them to make up their own minds on this issue.


Calculating gel doses when the math makes no sense


Doses of gels, because they are meant to experience such losses, can be really confusing. Manufacturers structure the stock dose iterations they market to take the losses into account and provide a specific delivered dose, so that makes them look wildly higher than other hrt forms when they really aren't. 

Beyond that, however, is the fact that because of this provided/delivered discrepancy, we can't just multiply the stock doses and have the delivered amount multiply accordingly. There's a dilution effect from multiplying the gel vehicle and a further effect upon drying/uptake time. This makes for some very counterintuitive math, but if, for example, you have the 0.5 mg dose packaging of some gels and take two of that dose, you can actually get a lower total quantity of delivered estrogen than if you took the same brand of gel in the 1.0 mg packaging. 

Yeah, this kinda makes our brains hurt too. One of our members has compiled a wonderful spreadsheet of all of the transdermal estrogens and what the various stock doses contain compared to what they actually deliver. That should help make things clearer when trying to compare a gel to other hrts in general coverage or when switching to or from a gel hrt. And yes, we'd normally expect our doctors to take this into account when writing our prescriptions. But in fact we've seen some notably uncomfortable miscalculations on the part of doctors as well as women, so it seems best that we should be able to double-check things for ourselves.


How to apply the gel


Since the gel dose delivery is based upon things like area covered and drying time, we need to be quite careful indeed to follow the instructions that came in the product information with our prescription. Further, because each of the gels in a given country are different, if we change brands for any reason, we need to adjust our technique to the correct one for the new brand.

Dose customization is possible but not facilitated by the way the gels are packaged and dispensed. Pump dispensers are reportedly not entirely accurate in amount dispensed already, so the idea of trying to measure out a partial pump strikes us as particularly prone to unreliability and inconsistency. Gel packets are also a problem to partition without measurement. While the tactic of transferring gels from either style of packaging into a syringe is always possible and would result in more accurate measurement, it's also a fiddly task that can result in wastage. Re-use of the remaining portion of a dose from even a capped syringe is also questionable, given how evaporation of the alcohol vehicle would affect the spread and drying of any held-over portion. 

Can we adjust our dose by manipulating our application technique? This seems likely, although difficult  to calculate with any assurance. The smaller the area the gel is spread upon, the more slowly it will penetrate into the stratum corneum because this isn't an instantaneous process. The smaller the area, the longer the waiting line to get in between each cell, if you will. In contrast, the wider the area of application, the thinner the layer so the shorter each "waiting line" is and the faster the overall dose uptake. 

However, we also have a drying time variable involved here, and that will to some degree offset this. For the smaller area, the gel will be deeper and hence take longer to dry; for the larger area, drying will be faster, thus providing a more limited time for the hormone to migrate into the skin. There will obviously be a small environmental component here as well, to do with humidity both in the air and in the skin.

In trying to use this form of dose tweaking, then, it makes sense to apply the dose as directed in the initial use of the particular hrt, starting with measuring out the intended application area (we don't know about you, but 5" x 7" is not exactly what we think of when someone says "small area"). This gives us a baseline at which we can hope we're getting the dose and dose dynamics indicated in the product literature. We should, as with all transdermals, try hard for application consistency as it is tied so closely to dose quantity. And then, once we've got 2-8 weeks consistent dosing, we should be able to use what we know about changes in application to fine tune our dose if that is needed.

Beyond that, how can we maximize the accuracy of our application? A number of the usual transdermal precautions apply. It should go on clean skin that has no other skin care products applied to it. The application area should not, however, be freshly scrubbed or overly warm (exercise, sauna, hot tub) because the open pores and enhanced surface circulation that heating causes will affect uptake time (in the direction of excess rapidity that might be uncomfortable) and perhaps quantity, since skin permeability will be affected. It might well also sting, since alcohol tends to do so under those conditions.

We've talked about not washing or wetting the area too soon and the need to wear clothing over the application area to protect others from accidental contact. But because of where the reservoir for this hrt lies, both on and in the skin, we also need to be very aware of other substances that can alter the uptake of the estrogen. This includes both things that are already on the skin when we apply the gel, which may either create a barrier to or foster enhanced uptake of the gel contents, and things that are applied after use, which may carry more of the hormone into our bodies than intended or block use of that dried reservoir atop our skin.

The patient information leaflet for Ostrogel cautions about interference of all of these products with gel use:

Skin cleaners and detergents e.g. products containing benzalkonium chloride or sodium lauryl sulphate, other skin products containing alcohol e.g astringents or sunscreens, products to treat skin and scalp disorders e.g. products to cure warts, acne or dandruff, other skin medication which change how skin is made, e.g. anti-cancer products
Now, sodium lauryl suphate is a surfactant used in many shampoos and body care products as well as most laundry products. But we have no way to know how much exposure to this is problematic: used to wash the area of application or generally used to wash one's body or transferable from our laundry? We just don't know, there's not data out there from the manufacturers, and we can't even find any useful published research.

Some of the skin care products the manufacturers seem most concerned about are sunscreen and moisturizers. This is a tricky class of products, in that there are many categories of formulations and it's not clear in which ingredients the problems actually lie. But the EstroGel product literature tells us this (emphasis added):

The effect of sunscreen and moisturizer lotion on estradiol absorption from 0.06% estradiol topical gel was evaluated in a randomized, open-label, three-period crossover study in 42 healthy postmenopausal women. The study results showed that repeated daily application of sunscreen for 7 days at 1 hour after the administration of 0.06% estradiol topical gel decreased the mean AUC0-24h (amount taken up in 24 hours) and Cmax (peak concentration of dose) of estradiol by 16%. Repeated daily application of moisturizer lotion for 7 days at 1 hour after the administration of 0.06% estradiol topical gel increased the mean AUC0-24h and Cmax of estradiol by 38% and 73%, respectively.

The effect of daily application of sunscreen/moisturizer lotion on estradiol absorption, when sunscreen/moisturizer lotion is applied before administration of 0.06% estradiol topical gel, was not studied.
And that's backed up by data on Elestrin, one of the other gels, where they found that a week of sunscreen use, regardless of whether it was applied before or after the hrt, effectively doubled the delivered dose. Their answer for this, by the way, is that we shouldn't wear sunscreen for seven consecutive days; no mention is made of what happens after six and a half days of sunscreen use or whether we're reset to zero effect after taking a day off. Head spinning? Yeah, we simply don't know enough about this dynamic.

What's interesting beyond just the application precautions in this is that we know from other research that sunscreen itself can contain estrogenic agents. Is that a factor here? We're not likely to know, since aspects of hrt efficacy are generally not tested to that degree. The only possible take-away from this all is to know that sunscreen can be problematic with any hrt, is especially problematic with transdermals, and definitely a problem for gel use. If a woman needs to wear sunscreen regularly, this may not be the hrt for her. On the other hand, for limited sun exposure, the fact that the gel application site already needs to be covered with clothing may be all that is needed to protect it and sunscreen use can be limited to only those portions of the body that are bared to the sun.

As for the rest of it, moisturizers and washing products, we just don't know how to advise you. The bottom line is most likely that trying it out with your own personal lifestyle is the only way to tell.

Don't expect your doctor necessarily to understand if you have problems with it, however, because they're not being given this kind of in-depth information in their training and will only come across it if they happen to read the product data sheets very carefully. For example, in the continuing education section of the website for the American Society for Reproductive Medicine, in an entry titled "HRT: Translating New Methods and Formulations into Patient Satisfaction" that is from a drug-company-sponsored symposium, it is explicitly stated that "Once absorbed, the gel is unaffected by the application of moisturizers or sunscreen." The symposium information also fosters the implication that any problems women have with this product are their fault, in that "some problems with adherence" is pretty much the only problem other than skin irritation noted in the use of gel hrt.



Final summary

  • We need to follow the application directions in the package insert for our own brand of gel scrupulously;
  • we should avoid anything that will wash the gel off within the first few hours after application;
  • we may need to be consistent about things that will heavily wet or wash the gel away as much as six hours later;
  • gels may not be suitable for very hot climates / heat exposure;
  • gels and sunscreen or skin moisturizers don't mix;
  • we need to read the instructions for and take precautions to avoid transferring the hormones in our gels to family members and pets; 
  • we need to think about the implications of washing off so much estrogen into the environment; and
  • our doctors may not have nearly this detailed a background into the complexities of using this kind of hrt.