Watching Women's Health

The safest form of estrogen in HRT

In recent posts on combination HRT, we've looked at how progestins affect breast cancer risk. Now let's consider an HRT risk more related to estrogen — venous thrombosis.

When an estrogen is taken orally, it is promptly metabolizied by the liver, stimulating a variety of liver enzymes. One effect of this liver activity is an increase in clotting factors.

Older women whose blood clots too easily have greater risks for heart disease, stroke and blood clots in the legs or the lung.

Our biggest study on hormone replacement, the Women's Health Initiative, looked only at an oral estrogen. The clinical trial arm of the WHI was stopped in 2002 because of increased risk of heart disease, stroke and venous thromboembolism.

In recent years, transdermal estrogen has become widely available. A big question is whether delivering estrogen through the skin has less impact on the clotting system, making it safer.

The ESTHER study, conducted in France between 1995 and 2005, compared transdermal and oral estrogen use in women with venous thromboembolism.

Compared to women not using HRT, women on transdermal estrogens had no increased risk of clot-related problems. Women on oral estrogen, however, had a 4 times greater risk.

Last year, a British Medical Journal report combined results from 17 studies on HRT and thromboembolism risk.  They found a 2.5 greater risk with oral estrogen. Again, women on transdermal estrogen had about the same risk as women not on HRT.

With combined HRT, it also appears progestins like norethindrone add to thrombotic risk, while progesterone does not.

So if you are considering HRT for menopausal symptoms, what's the safest regimen? Given the current information, I recommend the lowest dose transdermal estrogen that helps your symptoms along with cyclic Prometrium. If you've had a hysterectomy, you can skip the Prometrium.

Taking HRT this way for less than three years should relieve menopausal symptoms and be relatively safe for most women.

HRT and breast cancer - relative risks vary with the progestin

One of the newer pieces of information in the HRT puzzle is that risk of invasive breast cancer varies according to the progestin used.

A progesterone or synthetic progestin protects the uterine lining from overstimulation by estrogen that can lead to endometrial cancer. Women who've had a hysterectomy can safely take estrogen alone.

In a recent editorial, Dr Robert Barbieri summarizes some of the latest scientific information that might change how we prescribe hormones for menopausal women.

Ideally, we want to protect the lining of the uterus without adding to other risks. We do not yet have that ideal agent, but it's becoming clear there are different risks with the hormones that are currently available.

Combined information from a  French study and a German study, shows progesterone use minimally affected breast cancer risk. In the US, the only progesterone currently approved for endometrial protection is Prometrium.

With medroxyprogesterone, used in PremPro and as a separate tablet, the relative risk of breast cancer was 1.48. Norethindrone had the highest relative risk — 2.11.  Norethindrone is found in FemHrt, Activella, Combipatch and as a separate tablet.

It also appears using a progestin cyclically, rather than every day, carries less breast cancer risk because less progestin is used.

Continuous hormone regimens with daily estrogen and progestin were developed so women could avoid having period-like withdrawal flow. Now, with women taking HRT for a shorter time after menopause, avoiding withdrawal flow should be less of an issue.

For various reasons, some women do stay on postmenopausal HRT for longer than the 3-4 years now recommended.  For women on HRT for an extended time, it is especially important to update HRT regimens using our best information on risks and benefits.

Up next will be the safest way for postmenopausal women to take estrogen.

When does breast cancer risk increase with postmenopausal hormone use?

Most medical experts agree menopausal women on estrogen and progestin hormones for an extended time have an increased risk of developing breast cancer. The Women's Health Initiative (WHI) clinical trial was halted in 2002 after 5.2 years because increased breast cancer risk was found.

Yet some women have severe menopausal symptoms and can benefit from being on hormone replacement, at least for a time.

How long can women take combination hormones before breast cancer risk increases? Two recent reports address this question.

A Finnish report using national registry data involved 221,551 women on combination hormones for varying periods of time. Women taking hormones all received the same estrogen — estradiol — but were on a variety of progestins.

A progestin is used so the uterine lining is not overstimulated by estrogen.

They were divided into groups based on how long they took the hormones. The incidence of breast cancer in combination hormone users was compared to that of age-matched women in the general population.

For women using combination hormones up to 3 years there was no increased risk of breast cancer. After 3 years, increasing risk was noted with longer use. Women using hormones for longer than 10 years had the highest risk. 

Risk also varied according to type of progestin and whether the progestin was taken intermittently or continuously.  I will look at this topic in a later post.

A Boston University study also looked at when breast cancer risk increases with estrogen and progestin use. This study compared 4, 515 women with breast cancer to 18,058 age-matched women who had not been diagnosed with breast cancer.

These researchers found risk with estrogen and progestin use increased after 4 years. This study also looked at estrogen and testosterone combinations and found no increased risk over time unless a progestin was also used.

After the WHI results, most physicians have advised menopausal patients to take combination hormones for less than 5 years.  It now appears we should be even more conservative, as breast cancer risk may start rising after 3 to 4 years of hormone use.

The good news is women may be able to use estrogen and progestin hormones for a few years after menopause without adding to their breast cancer risks.

The big business of bioidentical hormones

Since a recent Oprah show about "bioidentical hormones," my clinic has gotten a flurry of calls about these custom-compounded preparations. And wow, these celebrity-endorsed, just-right-for-you hormones do sound good.  They are being promoted as a totally safe way to replace female hormones after menopause and slow the aging process.

But there is very little evidence these claims are true. Despite all the money being made on bioidentical hormones, hardly any is being spent to evaluate their actual effects.  Why not?  They are not FDA-regulated, so studies on safety and effectiveness aren't required. And they are selling just fine with endorsements and testimonials.

What are bioidentical hormones?  They are preparations of hormones found in women, derived from plants and altered in a laboratory into creams, gels or pills. 

They may include three forms of estrogen, progesterone, testosterone and hormones from the adrenal gland.  Often, a physician prescribes a special combination for each patient that is made in a compounding pharmacy.  

Hormones that are also essentially bioidentical are available in numerous FDA-approved prescription medications.  These medications are being extensively studied so physicians and patients can better understand their risks and benefits.

A recent news release from the American College of Obstetrics and Gynecology (ACOG) reaffirms their 2005 committee opinion that there is no scientific evidence to support use of bioidentical hormones. 

ACOG is the national organization for board-certified ob/gyn physicians.  It involves many of the best minds in women's health and is a leading source of current guidelines for practicing physicians.  I'd take ACOG's opinion over that of celebrity endorsers any day.

Another resource that discusses bioidentical hormones was published for consumers by the FDA.  No, the FDA isn't perfect, but it is one of our best lines of defense against potentially dangerous pharmaceutical preparations. When the FDA tested custom-compounded preparations, more than a third failed basic quality standards. 

The FDA wants consumers to know that claims about bioidentical hormones appear to be false and misleading.

Do we need better approaches to menopausal hormone therapy?  Absolutely.  But we will get them through careful study, not marketing hype.

Breast cancer risk decreases after stopping hormone replacement

We've been down a long and winding road trying to understand how best to approach hormone replacement therapy (HRT) after menopause. The road's direction changed dramatically when results from the Women's Health Initiative (WHI) were first released in July of 2002. 

Prior to the WHI, less rigorous studies had suggested replacing female hormones for an extended time after menopause benefited most women. It appeared that a possible increased risk of developing breast cancer was more than offset by significant protection against heart disease.

The initial WHI results contradicted that, especially for women taking both estrogen and a progestin during the 5.2 years of the study. Compared to women on placebo, combination hormone users had a definite increased risk of developing breast cancer and got no extra protection against heart disease.

Risks for women on estrogen alone are different — this post addresses only combination HRT including estrogen and a progestin. (Some women take both because a progestin protects the lining of the uterus from overstimulation by estrogen. Women who've had a hysterectomy can take estrogen alone.)

After the WHI, physicians prescribed HRT less often and many women discontinued use on their own. Breast cancer rates dropped in the US, starting In 2003 and continuing through 2005.

A new report from the WHI investigators suggests the decline in US breast cancer is almost certainly due to decreased use of combination HRT.  An earlier, alternate explanation, that lower mammography rates led to fewer diagnoses, appears not to be true.

The WHI results suggest a woman's breast cancer risk returns to baseline approximately 2.5 years after stopping combination HRT.

The WHI was a very large, well-designed study that has held up under prolonged scrutiny.  While only one type of estrogen and progestin was used in the clinical trial, increased breast cancer risk has also been found with other combination HRT regimens. It does appear that a progesterone may be safer than synthetic progestins, and that different progestins have different levels of risk for breast cancer. I'll look at those differences in future posts.

Why is combination HRT still prescribed? Some women have severe menopausal symptoms, mainly frequent hot flushes, that can effectively be addressed only with hormones. However, we now recommend the lowest possible dose of HRT for the shortest possible time.

HRT is a complicated topic that I will discuss frequently as new information becomes available. Later this week, I'll review a Finnish study that looked at how soon breast cancer risk increases with combination HRT use.