Breast cancer and hormone therapy

I believe that the most important influences driving our medical decision making process are our personal beliefs, both our worst fears and our fondest hopes. These belief systems are powered by our own medical histories, those of our family, the things that we read, and our personal experience. Sometimes my exam room is crowded to overflowing as Suzanne Somers argues with Dr. Susan Love in the corner as Dr. Andrew Weil tries to get a word in edgewise. Meanwhile my patient's mother and her best friend's cousin are lurking just behind her clamoring to add their opinions on the magazine articles spread out on the desk in front of us.

I would be foolish to discount these many voices; if they're important to my patient, they need to be a part of our discussion. I like to think my worst fears are highly informed ones, yet I am highly influenced by my family history of dementia and completely freaked out by the latest news on breast cancer and HRT in the latest issue of the NEJM(1). Here's the scoop:

The Women's Health Initiative randomized over 16,000 women to receive either combined postmenopausal hormone replacement therapy (Premarin plus Provera) or a look-alike placebo, then followed each group with regard to health outcomes, particularly the incidence of cardiovascular disease and breast cancer. The trial was abruptly halted in the summer of 2002 (what menopausal internist can forget that?) when it was clear that harm outweighed benefit with respect to heart attack, stroke, and breast cancer risk.

The study has come under attack for applying data obtained from a somewhat older group of women (average age 63) many of whom were overweight, hypertensive, diabetic, and smokers to a younger group of women just entering menopause and looking to improving their quality of life with HRT. Several studies, both trials concluded and some still underway suggest that, in fact, this latter group of 50-somethings may actually receive cardiovascular protection from the use of hormones particularly so-called bioidentical estrogen delivered in a non-oral fashion (such as via a skin patch).

I'm good with all that but note please that cardiovascular disease is not high on my to-worry list although I certainly recognize that many of my patients are at risk for same. And as losing my marbles is number one on my future frets, and estrogen is a top neuroprotective agent for aging female brains, I'm choosing to motor on with my HRT choices.

When the WHI data came out, some drug company or other provided me with graphics on this breast cancer thing. One thousand little grey female stick figures were lined up on the top of the page three of whom were colored orange. These unfortunate orange ladies were the number per year of new breast cancer victims in 1,000 post-menopausal ladies not on hormones. At the bottom of the page, another 1,000 skirted sticks queued up, 996 clad in grey and 4 in blue. You've got it: the blues were new cases of breast cancer per year in 1,000 post-menopausal hormone users. The absolute risk was huge; a 33% increase in breast cancer amongst hormone users but the relative risk small, namely one additional breast cancer per thousand users.

BUT...consider that 4th blue lady, her life turned upside down with biopsies, chemo, radiation, and a world of worry even though her chances of actually dying from that cancer are small. And if your worst fear is that cancer-induced world upheaval, then you will choose to discontinue therapy or never start it in the first place.

And now the doctors of the WHI bring us this new news to add to the evidence behind our worst fears, namely that the incidence of breast cancer which nearly doubled in the hormone users over the 5.6 years of the study decreased rapidly in the two years after the study coinciding with a marked drop in the use of combined hormones by the subjects. The busy slide at the top of this post illustrates this in the upsloping solid red line on the left which represents cancer incidence during the study and the soothing downward solid blue line on the right as fewer women got the bad news in the 2 years following the study's end. The black and white graph that follows is the interesting and contrasting data from a Scottish study that also notes the drop in hormone use over a similar time frame (the two plunging lines) but the more or less straight line at the top shows that Scottish women did not experience the drop in breast cancer rate with falling use of HRT.

Argh, what's an aging woman on hormones or contemplating their use to think? Estrogen is a growth-stimulating hormone, and thanks for the boost when it comes to bone, muscle, connective tissue, skin, vaginas, and brain. I love my brain power, I worry often about dementia, and I don't mind the youngish looking skin, so here's to hormones! But, breasts that aren't prepping to feed a developing babe don't like to be stimulated, and the more you goose your breast cells years after pregnancy is nothing but a distant memory, the more likely you are to stimulate a cancer. I don't want cancer, no not one bit, I know one woman who got cancer within 1 1/2 years of starting HRT, so to heck with hormones!

Well, Ms. Suzanne Somers staring out the cover of "The Sexy Years" like you just rolled out of a bed in which you were not alone, what is easy about this decision? Absolutely nothing. Per Dr. Morris Notelovitz, a venerable old menopausal researcher, every year a woman and her doctor should review her hormone therapy decision (and every other medical decision she makes per me!). If she is using HRT, why? If she is not using HRT, why not? What are the experts and your secretary's aunt saying? What do you believe is best for yourself?
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(1)Cheblowski, RT et al. Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women. NEJM. Volume 360:573-587 Feb. 5, 2009.

Estriol and wrinkles

Estriol is the darling of the natural hormone set. A weak little estrogen, it is, in fact, a metabolic byproduct of the normal breakdown of the body's two stronger circulating estrogens, estrone and estradiol. Enormous quantities are necessary to preserve bone mass, but itty bitty bits dabbed on your aging visage may improve the quality of your skin.

A .3% topical cream, available by prescription from compounding pharmacies, was applied daily to the wrinkled surfaces of a group of perimenopausal ladies. Not only did skin elasticity and firmness improve after six months of use, but also wrinkle depth and pore size decreased. Skin biopsy specimens (now how much did they pay these ladies for that?) showed increased numbers of collagen fibers. Serum hormone levels did not change and there was no evidence of any systemic hormone effects, suggesting that topical estriol is safe for use in women unable to use full-dose estrogen replacement therapy.

Estring and breast cancer

"If you run out of estrogen," a menopausal expert once told me, "you WILL dry up." As in symptomatic-genital-shrink-and-shorten sort of dry up. Yet many women are uncomfortable about the use of estrogen, particularly as it is associated with a slightly increased risk of breast cancer. For those of you passing up hormones or for those of you with a personal history of breast cancer, here's some important information.

Estring is a product that delivers estradiol locally right into the appropriate female passage via a silastic ring which is left in place for 3 months. During this time, the ring releases 2 mg of estradiol which is the equivalent of 1-2 days' worth of full-dose, oral estrogen therapy.

Menopause experts Drs. Nicole Brooks and Andrew Kaunitz note that they prescribe this treatment to a number of patients in their practices who are breast cancer survivors due to the ultra-low levels of estrogen that are absorbed via this route. Estradiol tablets--sold as Vagifem--are also effective in improving vaginal symptoms, but estrogen absorption into the general circulation is higher with their use compared to that with the ring. Some women complain of breast tenderness with the use of Vagifem. Estrogen creams produce the highest systemic levels of estrogen of all the local treatments and are sort of gooey.

While the estrogen absorption of Estring is ultra-low, the price is ultra-high.

Verbal fluency

Verbal fluency (VF) is defined as the ease with which a person can find the right word and use it at the right time. Verbal fluency tests generally involve a timed interval in which a person is asked to name as many animals (fruits, vegetables, words that start with Q, etc) as they can during that time.

I test my verbal fluency every day in the consultation room as I explain this, that, or the other medical condition to a patient with more or less ease. Progesterone definitely slows down my VF as does a lack of estrogen. Progesterone is known to have sedating effects on the brain, and my frontal lobe is clearly affected by my periodic use of Prometrium, a proprietary formulation of natural progesterone. A dose at bedtime gives me a great, dream-filled sleep but leaves me fumble-mouthed on the job the following day.

Likewise, estrogen has a strong influence on verbal memory, and some of my patients who choose to motor into menopause without HRT find their word-finding abilities seriously impaired. Estrogen supports the function of cholinergic neurons in the brain (those brain cells that communicate one to another via a neurotransmitter called acetylcholine). Cells in charge of verbal memory and executive functioning are cholinergic neurons and thus affected by lack of estrogen. Likewise, anticholinergic medication such as antihistamines (which are used as over-the-counter sleep aids) also can leave the user tongue-tied with respect to VF.

Not only does dementia cause decrease in verbal fluency, so often do head injuries (as the frontal lobe sitting just behind the forehead, is often first to hit the windshield in accidents), Parkinson's disease, schizophrenia, diabetes, and alcoholism. Persons with chronic lung disease are known to have cognitive troubles whether or not they're running short on oxygen levels. Ohio investigators found that 20 minute exercise sessions significantly increased verbal fluency scores on patients with COPD.

A nice-blended scotch of a pill?*

At least that is the market strategy of Wyeth Pharmaceuticals who will release Aprela within the next two years. This two-fer pill is Premarin wrapped up with Wyeth's new selective estrogen receptor modulator (SERM) drug called bazedoxifene or more lyrically by its brand name Viviant.

SERMs are molecules that are sort of estrogen-shaped and act more or less like estrogen at cellular receptors, turning their estrogen-based actions on or off. Currently available SERMs all have their good and their not-so-good qualities: Clomiphene hyperstimulates the ovaries to produce eggs for the infertile who take them. Tamoxifen blocks estrogen at the breast to prevent breast cancer recurrence but acts like estrogen on the uterus and can be associated with the development of endometrial cancer. Evista acts like estrogen on bone receptors thus slowing postmenopausal bone loss, blocks estrogen at the breast like tamoxifen, but screws around with brain estrogen receptors and can make hot flashes worse.

So the race is on to build a better SERM, and Wyeth is winning to be #2 on the market with Viviant having just been issued an 'approvable' letter from the FDA. So no big deal yet, just another SERM against osteoporosis competing with Evista. So here's Wyeth's ace-in-the-hole: one acronym...TSEC.

Tissue selective estrogen complex or the TSEC class of compounds was developed to offer a new menopausal treatent option "that, for the first time, partners a selective estrogen receptor modulator (SERM) with estrogens." The SERM protects the bones and uterus, the estrogen quiets the fire of the flashes. No information is available as to how the breasts fare in this mad dash for the estrogen receptors.
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*See April 28th post

Scot-free menopausal treatment?

We're not going to find a 'single-molecule' solution, so we're going to blend them — like a nice blended Scotch. You put it together, and you get something that, on the whole, will be better.
--David Barad, MD, director of assisted reproductive technology at the Center for Human Reproduction in New York City

Bring it on! I'm ready to settle into these golden years with a nice blended Scotch of a therapy. Check in later for a look at that which Dr. Barad rhapsodizes on.

HRT: NAMS is singing a new tune

In this day and age, the life span of any position statement is a maximum of 2 or 3 years. In the face of so much new information, we felt an update was due.
--Dr. Wolf Utian, Executive director of the North American Menopause Society

And their new position is that the benefits of hormone therapy outweigh its risks in healthy perimenopausal and early postmenopausal women with menopause-related symptoms and a low baseline risk of stroke.

Not forever, not for everybody

Hormones again in headline news, this time newsworthy by the the benefits of their absence.

Recent analysis of cancer incidence statistics for 2003 show a significant 7% drop in breast cancer cases for this particular year, the first full year of data following the abrupt termination of the Women's Health Initiative. Millions of women went off HRT as a result of the WHI data, and within a year, breast health improved.

While doctors acknowledge that cancers take years to form, they theorize that cancer cases may have decreased as itty bitty cancers that were forming in response to estrogenic stimulation shrank or disappeared. Indeed, the biggest decline was in tumors whose growth is fueled by estrogen--no estrogen, no support of tumor growth.

This news emphasizes the importance of individual decision-making in medical care. Any big decision--and to take hormones or not is a huge one--requires weighing many factors including personal and family health history, current symptoms, individual beliefs and worst fears, and future health goals.

Estrogen stimulates cell growth and repair. That is a good thing for neurons, muscle cells, osteocytes (bone), connective tissue, and healthy blood vessels. That is a bad thing for breast and uterine cells.

If a lack of estrogen makes a woman fuzzy-headed, sad, anxious, stiff, sleepless, or hot beyond belief, she may choose to use hormones for some indefinite period of time. If she has a family history of Alzheimer's disease, she may elect ongoing use. If she has a personal or family history of breast cancer, or if that is her worst fear, she may pass up HRT no matter how uncomfortable she is.

This is certainly dramatic news, and I will add this information into my discussions with menopausal women as they consider their plans for future care. I'm certainly taking it into consideration in my personal health care; for now, the pros continue to outweigh the cons in favor of ongoing HRT use. The patch stays attached into 2007!

I appreciate all of you who sent me e-mails regarding these statistics, and I look forward to talking to you about it as we adjust your therapies in the months to come.

Holding up those aging joints

I certainly noticed that the onset of flagging estrogen levels correlated very strongly with the onset of crumbling knees. Now we have a study that confirms the association between low levels of serum estradiol and a rising incidence of osteoarthritis of the knees.

In other words, the lower your estrogen levels, the higher your risk of knee joint degeneration. Read more in the upcoming issue of vintagefemail.

ET and the risk of breast cancer

As many of you know, I spend a lot of time reading about menopausal therapy. I not only want to give you the best and the latest information on traveling these middle years in health and style, I have an immediate and PERSONAL need to know.

No surprise that the heart of the hormone controversy is the association between breast cancer and the ongoing use of hormones after menopause. The Women's Health Initiative results released in 2002 clearly demonstrated that a combination of Premarin and Provera was associated with a slight but significant and increasing risk of breast cancer after four years of use. But data from the estrogen-only arm of the trial suggested that up to five years of use may be associated with a slightly decreased risk of breast tumors.

Information is now available from twenty-plus years and more than 28,000 nurses who reported on their use of estrogen alone and their incidence of breast cancer as part of the Nurses' Health Study. While use of estrogen for up to 10 years was indeed associated with a very slight decrease in breast cancer risk, the incidence of hormone-receptor positive breast cancer--which generally carries a more favorable prognosis than hormone-receptor negative cases--was significantly increased after 15 years of use.

Delayed cell death

Brain injuries, traumatic, toxic, or ischemic (lack of blood flow due to stroke or aneurysm) cause immediate cell death that is unavoidable. A secondary wave of death occurs, however, when cells adjacent to the damaged site basically commit molecular hari-kari. This secondary die-off is called apoptosis which means 'fading away,' an unfortunate event occurring in healthy neurons exposed to inflmmation.

Researchers have found in animal experiments that estrogen "dramatically" protects against this delayed cell death in brain injury. Neurobiologists at the University of Kentucky began the investigation by removing the ovaries of 100 rats, plummeting the unsuspecting rodents into menopause.

They then gave half the rats low doses of estrogen. After one week, the rats were subjected to an 'experimental stroke' as the researchers cut off blood flow through a cerebral artery. While estrogen did not protect against the initial cell death that occurred within hours of the stroke, it did markedly reduce the secondary damage.

The scientists have identified the mechanism by which the hormone protects the brain. They hope to develop designer estrogens in the future that have purely protective actions without any detrimental effects on body tissues such as the breasts.

An aging coed's hippocampus

Weird name for an important structure deep in our brain involved in memory. If yours shrinks with age, we know that your risk of Alzheimer's disease increases.

Dr. William Jagust of the University of California studied 59 women with MRIs to check out the size of their hippocampi. 46 were not on hormones and 13 were. He also scanned the brains of 38 men.

The women on HRT had significantly larger memory centers, roughly 10% bigger than those not on HRT and also larger than those of the male participants.

He continues to monitor the group to see if these mighty hippocampi protect against memory loss over time.

Bad vagina days

When you're out of estrogen, you're bound to have some vaginal discomfort. Breast cancer chemotherapy as well as the long-term use of estrogen inhibitors to prevent recurrence can plunge survivors into an endless string of bad vagina days. While oncologists have used low-dose local estrogen therapy such as Vagifem tablets or the Estring to counteract these BVDs, a recent study suggests this may not be a wise strategy.

London researchers studied six women taking aromotase inhibitors (Femara, Aromasin, or Arimidex) as adjuvant therapy for breast cancer. The women had virtually undetectable levels of estrogen before initiating therapy with Vagifem for four months. All the participants experienced a prompt and significant rise in their estrogen levels. While hormone levels dropped to baseline levels in two of the women, the remaining subjects had sustained elevations that were notably elevated in two.

The investigators concluded that "Using this vaginal form of estrogen which, we found, increases systemic estradiol levels, will counteract aromatase inhibitor treatment." The efficacy of aromatase inhibitors depends on near total suppression of estrogen causing concern among the researchers that long-term use of vaginal estrogen would increase the risk for recurrent cancer.

Reassuring news for the younger menopausal set

Investigators did a final sort through data from this trial that made headline news 4 years ago. They looked at risks of heart disease in younger women (ages 50-59) randomized to Premarin only or placebo. Women in this part of the WHI had undergone hysterectomies prior to entering the study so no progestogens were needed.

Women in this age group ordinarily do not have heart attacks no matter what they do, so the numbers of affected participants were small. Nevertheless, those in the treatment group were 40% less likely to have a heart attack or die from coronary heart disease compared with the group on no estrogen at all.

While experts still agree that HRT should NOT be used for heart attack prevention, these results are reassuring to women who choose to use estrogen for symptom control as they enter menopause.