In the news: Progestogens and lung cancer

Estrogen-only therapy may not up lung cancer deaths was the headline of  Reuters press release that came across our desk some time ago. According to the article, while the Women's Health Initiative Study showed that women in natural menopause taking conventional combined estrogen + progestin hrt had an increased risk for lung cancer (free signup required), women in surgical menopause taking estrogen hrt only did not show that risk elevation.

Interestingly, the research is mixed on this topic. An article "Dietary boron and HRT reduce lung cancer risk in women" published in 2008 in the American Journal of Epidemiology, stated that, based upon an "ongoing case-control study in Houston, Texas...[with]...763 women were diagnosed with lung cancer, and 838 were matched healthy controls with data on both diet and HRT," found that "HRT use was associated with a 31% reduction in lung cancer risk."

Okay, so how do we interpret this for our use? Does this mean we should quit using progesterone?

No, this probably doesn't mean that we can't or shouldn't ever use progestogens (progesterone and its synthetic cousins the progestins), but that answer may no longer be valid across all types of use in surgical menopause, so let's look at this a bit more closely.

Progesterone is different, isn't it?

First, let's set aside the whole "progesterone is natural so it doesn't carry this risk the way progestins do" issue.

So far as we have solid information on this, this statement represents nothing but wishful thinking. We have no serious population study data that differentiates between progesterone and a progestin, let alone between different progestins. There is one study, Progesterone--promoter or inhibitor of breast cancer, that says:

Similar to other progestogens, hormone replacement therapy with progesterone seems to promote the development of breast cancer, provided that the progesterone serum levels have reached the threshold for endometrial protection.

In other words, this seems to say that if we take enough of it to do us any good, the risk is severe enough to show up. Which doesn't mean that no risk accrues to lower doses, but rather that the effect could be more subtle or take longer to show up.  There's a unknown related to degree of use, here, that we can't yet fill in.

The WHI study was done with Provera, a specific progestin, and the results have not been checked in any large study against other progestins so we don't know—and analyses of the study results have pointed this out—whether this is a Provera issue or a progestin issue or a progestogen issue. Because one is taken as standing in for the whole, the media coverage and the doctors who get their continuing education from CNN will assume that it means all progestogens and panic accordingly. But each progestin has very different chemical characteristics and there is some reason to question whether this relationship with lung cancer is due to the elements progestogens have in common or an element Provera possesses uniquely. Until that distinction is made more clear, we really don't know. And until we do, we are as liable to panic and jump in the wrong direction as the right one.

So what should we do about this new demonstration of raised risks?

A lot probably depends upon how we use it

Now let's look at different categories of women and HRT use.

Women in surgical menopaue who do not have a uterus and who are taking plain estrogen, whose progesterone needs are being met adequately (as they define them) by their own progesterone production and the progestogens they acquire through environmental contamination, are shown by the WHI Study results as not experiencing this elevated risk. No one has suggested that they require hormone blockers to reduce their own progesterone production for further protection, which suggests that hormone levels appropriate to natural menopause with ovaries (which is what we emulate with hrt in surgical meno) are not presently interpreted as carrying this risk.

Women in surgical meno who do not have a uterus and who are supplementing both their estrogen and progesterone may be at an elevated risk level. As we noted above, we can't rule out risk based on the type of supplementation (progestin vs progesterone) at this time, so we can only work from the safer, more conservative position that increased progestogen exposure equates to some unknown level of increased risk.

But let's not get caught in the binary reasoning trap of research questions. This is probably not an either/or situation. That is, taking one molecule of a progestogen most likely does not slam us straight into the lung cancer risk category seen in the WHI. These women in the study who were on combined hrt were on levels of progestin designed to protect an intact uterus from developing cancer due to the estrogen stimulation. And they were on a fixed, study-mandated dose of estrogen, with no regard to their personal level of needs, especially at their age (they were women mostly in their 60s and up, taking a "standard" hrt dose for women a decade younger). So these women were being exposed to relatively higher levels of estrogen than we typically use in surgical meno if we are following the basic "as little as meets present needs" rule that is the current recommendation by the various medical specialty groups that have looked closely at all aspects of hrt use and menopause. In other words, they were taking a progestin at a therapeutic, not minimal-needs, level of dosing.

But that's not what we typically do when we supplement progestogens in surgical meno if we don't have a uterus. We take a dose only large enough to make up the shortfall between what we can produce and what our bodies need to balance out the estrogen we're taking. So the conceptual test we can apply here is that if women in natural menopause are not advised to have their ovaries removed and take hormone blockers to prevent their postmenopausal progesterone exposure, we may not be raising our risk exposure significantly when we simply mimic natural menopause with ovaries...as is the goal of surgical menopausal hrt. Now, we cannot promise you that this is entirely safe, but what we can suggest is that this seems reasonable based upon what we presently know.

But some women supplement to higher levels, and we're not sure how comfortable they should be about their risks. Who would do this? Many doctors prescribe high levels of progesterone to counteract excessive estrogen doses or to use progesterone as a hammer to bludgeon women on high or ill-fitting estrogens into being able to sleep. How high? Women who are taking 100mg or 200mg or even more of Prometrium or the equivalent are trending out of the supplemental range and into therapeutic dosing. And their risk picture is much less clear. They are approaching the level of supplementation that the WHI participants who saw that raised lung cancer risk were using, and that raises the question of whether they would be safer using some other approach for dealing with their problems than their therapeutic levels of progesterone intake. This is not a question we can answer yet, but it's probably one women should raise when they're looking at these higher progestogen doses.

And finally, the third group of women: those required to use therapeutic progestogen doses to treat some other risk. These would include women in surgical menopause who retained their uterus, or women with endometriosis. They must take more than a balanced dose to produce this therapeutic effect, and this places them right into the WHI risk profile.

So how can this set of risks be managed? On the one hand, we can look at relative incidence of endometrial cancer and compare it to the lower risk of lung cancer. Are there modifying factors? Surely familial history and smoking exposure will also play into the lung cancer side of things, yes.

Is there anything these women can do to lower their overall progestogen exposure and still obtain the benefits of therapeutically effective doses where they need it? Yes, in fact there is: use of a vaginal progestogen provides higher levels in pelvic circulation, where therapeutic effect is needed, and less in general circulation, where it is not. There's more information on this in our discussion of hrt for women with a uterus but no ovaries, as well as in a discussion of a news article about contraceptive patches.

While we don't know what "safe" is in this context, surely whatever we can do to lower our exposure risk until it's better understood is at least doing what we can to approach safer.

The bottom line

We don't have enough information yet to be able to draw any sort of safe-or-not line. We may never have this: research isn't about what we want to know; it's about what someone will fund a study to find out, and that's often dependent upon who thinks they can make money from its results. At the moment, though, this correlation between progestogen use and several types of cancer suggests that we should use only as much of any progestogen as we demonstrably need, and it probably makes sense that we should do what we can to limit our systemic as opposed to therapeutic exposure.

Should we panic and give up progestogens entirely? Oh goodness no: we don't begin to know enough to say this, and even the risk factors as they stack up don't begin to suggest that level of panic is necessary.

Should we figure that because progesterone is a natural hormone manufactured by our own bodies that it's safe? Nope, not this either: we know that our own estrogen poses cancer risks that we can reduce by controlling our exposure, and this may well turn out to be the same sort of situation. So no, the old Dr. Lee premise that you can't have too much progesterone is looking as shaky as those 1950s articles touting estrogen as the magic agent to keep us "forever young."

Hormones are active agents that are active throughout our bodies. Something this active is never likely to fall into entirely-safe territory. What we need to learn and can hope that research will begin elucidating is just what the parameters are of the risks that progestogens pose. Only then can we make sound decisions between our various risks to make sure that we're only engaging in the ones we deem acceptable for the benefits gained.

HRT for those with a uterus but no ovaries

Although this site focuses mainly on those who have had both an oophorectomy (ovaries removed) and hysterectomy (uterus removed), some individuals choose to have diseased (or high-disease-risk) ovaries removed and yet retain their (healthy) uterus. Others who might fall into this category are those who have sustained such a severe chemical menopause due to cancer treatments that they are now without functional ovaries although they remain technically intact.

While they will experience the same issues to do with choosing hrt as those in full surgical menopause, the need to keep their uterus healthy must also be taken into account and this will change their ultimate hrt options.

The crux of the issue is that exposing a uterus to estrogen stimulates the growth of the uterine lining or endometrium. In our fertile years, this stimulation is necessary to prepare the uterus to support a fertilized egg. When no pregnancy occurs, our hormone balance naturally cycles to cause our unused uterine lining to be shed in the form of menstrual flow, resulting in a period.

But when we no longer have ovaries to manage this cycling, uterine health becomes an issue. If we fail to shed that lining, it can build and build and over time, this unshed lining may turn to uterine cancer. Yeah, that's bad. It's so bad that it's a fundamental rule of hrt use that anyone with a uterus must include provisions in their hrt to prevent this from happening.

Like what? There are two basic strategies: we can artificially create a hormone cycle with our dosage pattern, thus causing the lining to shed regularly in a period OR we can balance our hormones in such a fashion as to suppress that lining buildup in the first place, eliminating periods. Let's look at both of these a little more closely.

Hormone cycling

This is the classic approach. We take an estrogen hrt for part of the month and add some sort of progestogen (progesterone or a synthetic version that acts like it) for a shorter time, often a week to ten days, to stimulate a period. Many individuals find this sort of cycle reassuring, since it mimics what they experienced in their fertile years. Many doctors prefer it because they feel that their patients do best with what they are accustomed to or that they are less likely to become confused keeping track of their hrt on a short schedule.

This kind of cycling does carry a cost, however. If you suffered through PMS or your monthly cycle of ups and downs with mood swings and bloating, maybe going on doing that doesn't sound all that appealing. Maybe you would be just as happy to make fewer trips down the feminine products aisle at the store and wear more white underwear without fear. Maybe you'd like to balance uterine protection with a little more comfort and freedom from that cycling.

There is nothing magical about monthly cycles once our ovaries aren't controlling things. Research in recent years has found that we really only need to cycle a few times a year to preserve uterine health, either using oral contraceptives (while we are in our fertile years) or hrt (when we are post-fertile for whatever reason). A conservative schedule for this long-period cycling would be quarterly, although some individuals find that they can successfully go even longer without undue risk. So long as they are not having break-through bleeding (which indicates that their lining is building up beyond normal levels), they only take a progestogen every three or four months to produce a period. This requires keeping track of this schedule so we doesn't go too long without completing that cycle and it requires that we use separate estrogen and progestogen hrts—neither of which are necessarily difficult to achieve. There will still be the same ups and downs of cycling and anyone using this approach will still have periods, but they'll happen less often.

Is this strategy appropriate for all of us? Not necessarily. Those of us with endometriosis, for example, may find that this is still too much estrogen stimulation. Those with cancer risks or metabolic disease or risk factors for blood clots may not be best served by this sort of a dosing scheme. Maybe you don't consider having periods or hormonal cycling an important part of your identity at all. This is one situation in which each individual needs to sit down with their doctor and consider carefully all of the factors that are involved in their use of hrt.

Continuous combined HRT

The other approach to uterine protection involves suppressing the growth of that uterine lining by continuously and simultaneously taking both estrogen and a progestogen. The lining never has a chance to grow, so there is no need to have a period to shed it. Hey, that sounds pretty good, doesn't it?

But there's a cost, and that cost might not suit every one of us. In order to accomplish this, we must deliberately induce a hormone imbalance. We have to take more of that progestogen than we really have a need for otherwise to balance our hormones. Or, to put it another way, we need to have a deliberately progesterone-heavy balance.

For some, that's not a problem: they're perfectly comfortable with a standard dose of any of the retail progestogens made for this purpose.

Others, however, find this balance subjects them to an uncomfortable excess of progesterone effects. For them, then, the challenge is minimizing those effects while still providing the protection that their uterus needs.

And, finally, some are increasingly concerned about the risks of progestogen use that have been revealed in the past couple of decades of hormone research.

Luckily, there is more than one way to approach this problem. If we are going to use a progestogen in a continuous, imbalanced manner, it's worth trying different progestogens to see if one is less unpleasant in this regard than another. Amongst the progestins, each one is very different in structure and characteristics, and will act differently in the body. So if this is your choice, it may be worth auditioning a variety of them. Route may also make a difference, so even if your choice is progesterone itself, taking it via a different delivery route may also help you manipulate its effects.

But another way of dealing with this—and especially with the risks—is to maximize the impact of your progestogen on your uterus while minimizing it elsewhere. This is done by using a more local delivery, either via the vagina or the uterus itself. This way, the highest levels are experienced in the pelvic organs, where they're most needed, and less of that dose makes its way to systemic circulation, where it's not needed. In fact, one source suggests that this can represent a pretty significant difference:

Furthermore, vaginal administration of micronized progesterone has been shown to enhance progesterone delivery to the uterus by about 10-fold in comparison to im injection, despite the markedly higher (about 7-fold) circulating drug concentration achieved with im injection.

Further, this technique is specifically cited by the International Menopause Society in their 2011 position statement as having particular merit.

Sound interesting? There are actually several different hrts that provide for local delivery. Prochieve is a progesterone gel specifically designed for vaginal use, but some individuals have reported successfully inserting a Prometrium gelcap vaginally and allowing it to be absorbed that way (typically, overnight). Vaginal suppositories such as Endometrin are also available, as are versions that can be custom-made by compounding pharmacists. And Mirena is a progestin-releasing IUD that works directly in the uterus and so can get by with an especially low level of dosing.

We also have come across some interesting information that indicates that at least some progestins may be capable of transdermal delivery--something we probably could have put together before given that contraceptive and combined-hormone hrt patches aren't exactly new. That raises the question of whether certain of the progestin hrts meant for oral delivery could be used vaginally (at a suitably lower dose). We don't know the answer but it seems to be something that might be worth looking into if using a local progestin by other than IUD would be your preference. More on that in this news discussion.

Will I have to do this the rest of my life?

No. You will, however, need to tailor your hrt for uterine protection so long as you take enough estrogen to stimulate your uterus.

Our hormone needs diminish with age. For that reason, it's a good practice when taking hrt in any form of menopause to challenge ourselves every few years to be sure that we're taking no more than we truly need to achieve the effects that we define as important. By trying out a slightly lower dose every 3-5 years, we can find out if our bodies have been slowly easing down in needs without us noticing.

In theory, we'll all, if we live long enough, reach a point where our hormone needs are low enough that we no longer need to supplement with hrts. What we produce ourselves plus what we take in from foods and environmental contaminants will fully meet our then-current needs. And when that happens, we're probably not stimulating our uterus enough to need to continue to provide progestogen protection for it. That's something to review with one's doctor, of course, but that's the expectation. Until that time, however, so long as we've got a uterus and are supplementing estrogen, we need that progestogen coverage as well.

How will I know I'm taking enough progestogen?

You won't. The general guideline is to look for spotting. This is taken to mean that your lining is growing enough that the progestogen isn't providing adequate suppression, whether you're taking it cyclically or continuously.

If, however, you have a high risk situation where you aren't comfortable waiting for this symptom to tip you off, there's another method for monitoring uterine lining response: ultrasound measurement of the thickness of the uterine wall. This can be ordered by your doctor, is a bit uncomfortable but generally not painful, and if properly coded should be covered by most health insurance.

There is not, regrettably, any magical formula for relative doses, such that if we take this amount of estrogen, we know we'll need that amount of progestogen and then we'll be sure we're safe. Or if we have this measured level of circulating estrogen, we need that level of circulating progesterone to cover it. Hormones don't behave in a simple relationship like that—there are many other factors that can affect our hormone supplies and relationships. We can't force our hormones to go where we want and do our bidding. What we can do is provide the supply and then watch carefully to see what happens. If what happens is no uterine lining shedding, no spotting, then we most likely have the situation covered. And if we don't, then a simple ultrasound will tell us how our uterus is doing and whether we just have a brief unusual situation or whether we need to tweak our doses.

Let's repeat that, because it's pretty important: the test of our hormones is not in what we want them to do, but in what they actually do. Results are the most reliable place to focus our vision.

So that's it?

Yeah, pretty much. Outside of protecting a uterus, our other hrt needs are essentially the same as for those without a uterus: meeting our post-fertile needs as we define them while exposing ourselves to the least amount of risk possible. So the information on hrt-balancing that is covered elsewhere on this site is just as applicable to you as it is to the those in full surgical menopause.

Got questions? Other concerns? Join us at our discussion forums.