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 not to long 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. We also have an article "Dietary boron and HRT reduce lung cancer risk in women" published in 2008 in the American Journal of Epidemiology 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. We do have 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, 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 meno 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 usually 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 would never be 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.