A woman traversing the menopausal transition must nowadays feel like the rope in a tug of- war, being pulled first one way and then another by conflicting media accounts and shifting “expert” medical opinion. The only light she sees at the end of the tunnel is the light of the oncoming train!
Should estrogen be supplemented in the peri- and postmenopausal woman? What are the advantages and disadvantages of estrogen “…forever” and “…never”. What are the effects of HT, and for that matter hormonal withdrawal, on the cardiovascular and immune systems, cognitive function, bones, breasts, etc.? What are the long-term consequences of taking, and of not taking, HT?
THE DAMNING OF HORMONE THERAPY
A new player has emerged in healthcare decision-making. It is not the patient or the doctor. Nor is it the third party payers, hospitals or other healthcare providers. It is the media, as well as putative “experts,” whether they be writers, so-called pundits, or selfproclaimed on-line specialists.
It is revealing that, when the initial phase of the Women’s Health Initiative (WHI) Study was (mis) reported in July, 2002, these were the sources that immediately climbed on the carnival bandwagon, while the true experts in the North American Menopause Society (NAMS) and elsewhere quietly studied the data–all the data, WHI and otherwise, and soberly, as early as the fall after that summer’s bombshell, realized that, although some useful information emerged from it, the WHI was a flawed study that did not show most of the terrors the media was reporting.
What happened here? A study designed to follow the cardiovascular effects of HT initiated in older women well past menopause churned out statistics that appeared to show that if one combined oral estrogen and a strong synthetic progestin in doses high for their age, that there appeared to be an upward trend in breast cancer. Perfect “fear-factor fodder” for the media!
Two years later, in the fall of 2004, data from the second phase of this same study was reported by the same investigating team. These data showed that for the group of women who took estrogen only (without a progestin) for 7-1/2 years (over two years more than the first group) there was no increase in breast cancer. That news had a one-day 3 rd page run.
Simply stated, to quote cardiovascular researcher, Howard N. Hodis, M.D. of USC, “The WHI trials simply missed the boat, as did all of the other randomized trials of the same genre…”
Why did most physicians with the notable exception of menopausal practitioners and hormonal experts, who took the time to carefully study the data and found it bogus, tell their patients to “stop hormones?” Because, it is easier to “just say no” (and be medicallegally safe) in three minutes than to take many hours studying the data and then the time necessary to individually counsel each patient.
Over 65% of women on HT stopped and many became miserable. In the years to come, increased incidence of cardiovascular disease, osteoporosis and Alzheimer’s will reflect that decision.
There is certainly another force leading the lynching of estrogen therapy–that of the illinformed, under educated, often “true-believing” para-medical huckster. Think of how many more millions (? Billions) of dollars were spent on secret “proprietary” supplement blends, progesterone cream, botanicals and neutraceuticals–all unstudied and potentially dangerous–by scared, hurting and hot flashing women newly off estrogen therapy. These folks, many on-line, fattened their pockets with the philosophy of “…well, if we know nothing about it (these non-studied supplements and cream) they must be safe…”
THE PRESENT TRUTH ABOUT HT: ESTROGEN, PROGESTERONE, AND TESTOSTERONE
It’s all about the estrogen! Virtually all of the disconcerting changes of (peri-) menopause involve initially wild swings and eventual loss of this hormone.
Most large, well performed studies, including the WHI, have established that estrogen is a preserver of function when begun in a “window of opportunity” during or relatively soon after (the sooner the better, but certainly within five years) the menopausal transition. It is not a repair of bad function if started well later (as shown by the WHI and misinterpreted by both the pundits and media to incorporate all women).
What do we truly know about estrogen? What are the pros and cons?
All large observational studies, the Nurse’s Health Study, the subgroup analysis from the WHI of early postmenopausal women and many others, confirm a statistically significant beneficial effect of HT on long-term cardiovascular health. Women who have taken estrogens for ten years or more and have started around the time or soon after menopause have statistically less cardiovascular disease.
Data also show a neurologic benefit when HT is started in recently menopausal women. The MIRAGE and several other large epidemiologic studies demonstrated an up to 65% decrease in Alzheimer’s disease risk in postmenopausal women using HT versus those who did not. (The WHI showed that HT perhaps increased the risk of dementia and cognitive decline when therapy was started over ten years after menopause).
Estrogen (testosterone too) prevents bone loss and greatly decreases the risk of osteoporosis. Estrogen prevents colon cancer to the same degree as the suspected increase in breast cancer risk.
On average, collagen is more pliable in women taking estrogen. Memory and mood are better. Postural balance is better (less fracture risk). Stress is reduced secondary to better sleep, less hot flashes and anxiety, etc. New data also suggest that women who were compliant with HT through a five-year followup were one-third less likely to develop diabetes than a placebo group. (Data from WHI and HERS studies). Data from a recent study from Rogerio Lobo’s group at Columbia demonstrate that short-term transdermal estrogen therapy (but not oral) resulted in improvement in obese postmenopausal women with metabolic syndrome.
The greatest risk for breast cancer (outside of genetics, obesity and a high animal-fat diet), appears to be long-term exposure to high estrogen and progesterone levels by many years of menstrual cycling. Continuing with many years of combined (estrogen plus progestogen) HT leads to a very slightly higher risk of breast cancer, and it appears that the risk is magnified by a progestin compared to Progesterone as the progestogen source. Utilizing estrogen alone, especially low dose, and utilizing a progestogen cyclically every 2-6 months increases risk much less, perhaps only 3-4 per 10,000 women per year, beginning only after many years (? 7, ? 10) of continuous therapy. This risk may be less for transdermal than oral therapy.
What about thromboembolism? We all “know” from numerous well-conducted studies, that estrogens increase the risk of stroke and thrombosis. But technically we are wrong. Until recently, all of these studies were performed only with oral estrogens. Recently, two large, well-controlled studies were performed, comparing low-dose and high dose transdermal estrogen (via patches), and oral estrogens, with a control group. There was no difference in thromboembolism between control and low dose transdermal estrogen group, with oral estrogens having the highest risk, and high dose patch in between.
This should come as no surprise since metabolism of oral estrogen releases both clotting factors and SHBG. Transdermal estrogen, via direct absorption, bypasses the liver on its most potent “first pass.”
This “confounding factor” should not surprise us. It also shows that no one, certainly not the pundits or the press, should take “medical study” results at face value until they have carefully investigated their source and veracity.
Most experts agree that the now (in)famous WHI, which so scared patients and their physicians that > 65% of women stopped their hormones, overstated the risks for the majority of women using HT. When investigators separated data from the women who started HT in their late 40s and 50s (not mid-60s) many of the health risks didn’t show up.
“There is a fear factor,” says Wulf H. Utian, M.D., Executive Director of NAMS, “The fact is that virtually everybody agrees that for the majority of women, two to three years of hormones are helpful to relieve symptoms. But that sort of information has not trickled down to the consumer.”
Testosterone frequently has a place in therapy. An oophorectomized woman loses roughly 50% of her testosterone. Why don’t docs remember this when they prescribe estrogen, but not testosterone, after hysterectomy?
Testosterone falls also through menopause and replacement of very low amounts (1/10th- 1/20th of that given to men) frequently reduces symptoms.
Testosterone for women is underutilized by rank and file physicians. Although it is available by prescription in several forms the politicized FDA has yet to approve a transdermal form for women and usually it must be compounded, a skill that many frontline physicians do not have. Relying on the compounding pharmacists to do the formulating and dosing with a “rubber stamp” okay from the clinician is risky and frequently results in overdosing.
HORMONE THERAPY AND WOMEN AT RISK FOR BREAST CANCER
HT generates a knee-jerk response from both the public and clinicians regarding its relationship to breast cancer. “It caused it”; “It will make things worse”; “…don’t even think about it!”
The realities and the statistics tell another story. In a well-researched meta-analysis of more than 45 studies involving over 750,000 high risk and breast cancer surviving women, well-respected epidemiologist Dr. Trudy Bush found that, as a blanket statement, estrogens do not cause breast cancer. In fact, if a woman with a previous history of breast cancer takes short-term (1-1/2–2-1/2 years) low dose HT, she has a decreased risk of dying from both breast cancer and cardiovascular disease than a woman who does not take estrogens. Additionally, her passage through the sudden chemotherapeutically-caused menopause that follows and her ability to weather the transition, the cancer, and be strong and immunologically whole is markedly improved.
There is no reason to deny breast cancer surviving women and women with increased risk of breast cancer low dose, rapidly tapering estrogen therapy (and testosterone as well) to soften the menopause transition and improve quality of life.
Many oncologists, however, will not even hear of any program which smells of any HT whatsoever, even if it is short term with a rapid taper. The old teaching is, no HT, ever. Unfortunately, Quality of life may not enter into the decision-making process.
If a woman is on hormone therapy at the time of breast cancer diagnosis, there is no rational reason why she cannot gently taper off the HT over a period of 6-12 months (not “cold turkey”) while beginning chemo or radio therapy. Botanicals and supplements and non-hormonal meds to temper hot flashes, preserve mood, help with sleep, etc. may be tapered in at the same time. Vaginal estradiol may be used as needed for dryness. The dose is low and the amount absorbed systemically so limited, that even oncologists rarely have a problem with this.
Additionally, there is no convincing evidence to withhold HT from women at increased risk for breast cancer, or in long-term breast cancer survivors. The key: Low dose; limit the progesterone (cyclically); add in low dose testosterone if warranted, and screen regularly (self exam and mammography).
Summarizing, what do large evidence-based studies, observations and intuition tell us:
1. Botanical supplements may help mild symptoms but most recent large studies show their effects to be mostly placebo related (which is not bad). However, they rarely work for severe symptoms.
2. The NAMS 2007 Physician Statement, soberly arrived at by true experts in the field, supports the use of HT for menopause-related symptoms and disease prevention for appropriate populations of peri- and postmenopausal women.
HT may be utilized for the menopausal transition only, for 2-3 years, tapering off to zero over a six-month period or may be used for a longer length of time. If started during a “window of opportunity” as close to menopause as possible (preferably within 3-5 years after last period) and continued for over five and preferably over ten years, HT confers several health benefits, including significant protection in the area of cognitive function, cardiovascular disease, diabetes, bone density, improved mental health and colon cancer. The benefits far outweigh the small increased risk to the breast. There is a lot to recommend prolonged (> 10 year) low dose therapy.
3. All recent data support the increased safety and effectiveness of non-oral (transdermal; transvaginal) therapy. Transdermal is safer and more effective than oral!
4. Low-dose unopposed estrogen is safer for the breast than combined with progestogen, but unopposed estrogen raises a potential risk for uterus; administer adequate dose progestogen in 10-14 day cyclic pulses, every 2-6 months if HT is to be continued past 1-2 years.
5. Uncomfortable, hot-flashing, moody, sleepless persons are stressed. Chronic stress and anxiety is associated with immune dysfunction, abnormal cortisol levels, diminished memory, increased cognitive dysfunction, increased Type II diabetes and metabolic syndrome, and depression. HT leads to less chronic stress by mitigating causative symptoms.
So, what did the media and the so-called medial pundits (and thousands of misguided primary care physicians) accomplish when they took their patients off HT several years ago (and to this day remain hesitant to restart). Well, they probably saved several thousands of cases of hormonally dependent breast cancer (75% of which would have been cured anyway), and caused hundreds of thousands of needless deaths from cardiovascular disease not to mention the many-fold greater hip and other fractures from osteoporosis and longterm care admissions from Alzheimer’s. Score one for the knee-jerk response!
New Data on Migraine and Menopause
Migraine is a common and frequently disabling condition whenever it occurs. As fluctuations in female hormones can have a profound effect on women who are susceptible, one would expect sequelae from the hormonal rollercoaster that accompanies the perimenopause and early menopausal years.
Women are three times more likely to suffer from migraine than men. The cyclical changes in hormone levels are a key trigger, explaining the worsening of migraine commonly see just before, during and after menses.
There are two types of hormonally-sensitive migraine sufferers. Those who experience their headaches during estrogen withdrawal (menses; “off days” of oral contraceptive pills; the lowered hormonal levels of menopause), and those whose migraines worsen when estrogen levels are increased (e.g. after starting oral contraceptive pills or postmenopausal hormone supplementation). This hormonal sensitivity may explain why migraine worsens around time of perimenopause, when estrogen levels fluctuate and decline.
Two-thirds of women’s migraine improves within a couple of years after menopause, although approximately 10% experience worse headaches and approximately 25% notice no change.
Because of the migraine’s schizophrenic reaction to hormones, there is no way of knowing which women will respond positively and which poorly to menopausal hormonal supplementation.
ALL ABOUT MIGRAINE
Modern theory is that migraine is a brain and not a vascular disorder, a disorder of “sensory modulation” with increased sensitivity to sensory input, pain, light, sound, smells and head movement.
A family history of migraines suggests a genetic component. Patients who are genetically predisposed are “triggered” with changes in external or internal environment (sleep alteration, stress, hunger, temperature changes, etc.).
What is a more intimate part of a women’s internal environment than her hormones? Estrogen and progesterone can profoundly alter neurotransmitter (brain enzyme) levels of dopamine, serotonin, etc., effecting the genesis of headaches. Estrogen withdrawal has been shown to alter the levels of several blood proteins, all of which play a role in pain modulation.
The majority of headaches that worsen during peri-menopause are secondary to migraine. Migraines are usually one sided, throbbing, aggravated by movement, light and sound, frequently accompanied by nausea and vomiting, and are of moderate to severe intensity.
MANAGEMENT AND PREVENTION OF MIGRAINE
Treatments may be divided into two categories: Acute (getting rid of the headache once it has started) and preventative.
Acute, first line therapies, other than general lifestyle changes such as relaxation techniques, exercise, and avoiding triggers such as alcohol, may be classified into nonmigraine specific and migraine specific.
Aspirin, Tylenol, ibuprofen (“Advil”), Naprosyn (“Aleve”), etc. may be ingested at therapeutic doses (e.g. three-four over-the-counter ibuprofen; two-three “Tylenol Migraine, etc.” at the first hint of a headache. If complete relief is not obtained within 30 minutes, other non-specific medications such as Fiorinal/Fioricet or the narcotic analgesics codeine, Vicodin, etc. should be taken, or the migraineur may proceed directly to “migraine specific” meds such as one of the triptan or ergot medications. The triptans (sumatriptan or Imitrex, rizatriptan or Maxalt, etc.) serve to increase serotonin in the brain and are the mainstay of acute migraine-specific treatment for patients with disabling attacks.
One should be careful, however, with the frequent use of non-specific remedies such as Tylenol, caffeine, codeine and Vicodin, as using such compounds over two or three days per week is probably sufficient to induce chronic “rebound” headaches.
Someone with frequent headaches (two or more per week) requires a preventative therapy, not additional acute attack treatments. Preventative therapy means that medication should be taken on a daily basis, whether or not there is a migraine; the idea is to reduce the frequency and severity of each attack. Preventative medication may be used in conjunction with acute treatments. These medications include propranolol (Inderal), tricyclic antidepressants (e.g. Elavil, etc.), valproic acid (Depakene), gabapentin (Neurontin) and others. Estrogen as well can be considered under the heading of preventative therapy in women.
Hormonal supplementation does not increase the risk of stroke in patients with migraine. If a woman complains of classical menopausal symptoms as well as worsening migraine, its reasonable to start HRT. A transdermal preparation (patch or cream) may be less likely to exacerbate headaches than oral, especially if the oral is conjugated estrogens (Premarin).
If hormonal supplementation significantly improves menopausal symptoms but causes worsening headaches, a step-wise reduction in dosage (instead of stopping the HRT) may resolve the situation. If this fails, the estrogen type should be changed. There is evidence that converting from conjugated estrogens to pure estradiol, from a synthetic to a bioidentical (especially transdermally) may help.
If alterations in the estrogenic component of HRT are unsuccessful in improving headaches, similar alterations may be made in the progestagenic component, lowering dosage, switching from a progestin-like medroxyprogesterone (Provera) to norethindrone or bioidentical progesterone orally (Prometrium) or vaginally.
Since withdrawal of estrogens can exacerbate migraine (this is seen pre-menopausally in women who have so-called “menstrual migraine,” which is well treated by adding in a small dose of estrogen during the menses), peri- and postmenopausal women are perhaps better treated with continuous, rather than cyclic, HRT. Since the progestagen given along with the estrogen in women with an intact uterus can worsen headaches in some migraineurs, giving the progesterone cyclically (every one-four months) may improve symptoms.
The bottom line? Every woman is an individual, including a woman with migraine. You shouldn’t have to suffer! Have your health care practitioner work out a regimen to fit you.
Reference: “Migraine, Menopause and Beyond” by Miles J. Levy, M.D., and Peter Goadsby.