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Where did my memory go? Cognition and Menopause
Many women around the time of menopause complain about impaired memory, and many are worried they are developing dementia. Fortunately, for most women, this lapse in memory is more related to stress and sleep deprivation than a true cognitive decline. A leading expert in estrogen and cognitive function, Dr. Victor Henderson from Stanford University, stated at the NAMS meeting that although subjective memory complaints are very common around the time of natural menopause, objective memory deficits (documented by testing) are NOT common during midlife.
Dr. Roberta Diaz Brinton, a scientist in the School of Pharmacy at USC, discussed the “healthy cell bias” hypothesis of estrogen action. Her studies have shown that estrogen initiated while the nerve cell (neuron) is still healthy, prior to insults such as free radicals, β-amyloid, ischemia or excitotoxicity, actually helps preservation of neuron function and increase their survival. Estrogen-induced pathways lead to generation of ATP (energy) in mitochondria of neurons. On the other hand, if a neuron that is already diseased by afore-mentioned stresses is given estrogen, estrogen actually increases neuron degeneration. This finding helps explain the adverse findings from the memory substudy of the WHI (Women’s Health Initiative) indicating that women treated with CEE-MPA (Conjugated Equine Estrogen-Medroxyprogesterone) had a higher risk of developing or progressing dementia. However, there is evidence that early initiation of estrogen therapy reduce the risk of cognitive decline. These findings support the “critical window” hypothesis which indicates estrogen begun later in menopause do not benefit any cognitive outcome and may actually be detrimental, whereas early initiation of estrogen may reduce dementia risk. This “critical window” for initiating estrogen therapy is also seen in vascular health.
Anxiety, Depression, Mood and Menopause – How are these linked?
Dr. Bernard Harlow from University of Minnesota presented findings on the risk of depression during the menopause transition. In women with no history of depression, women in perimenopause had 1.8 times the likelihood of experiencing their first episode of depression, and this risk is associated with the presence of vasomotor symptoms (hot flashes/night sweats). Women with a past history of depression who experienced recurrent episodes prior to menopause transition were much more likely to experience recurrent depression after menopause (86% chance) compared to women with only 1 episode of depression prior to menopause transition (58.2%). Interestingly, anxiety and depression seem to affect the timing of menopause. Women with history of depression with significant depressive symptoms at midlife enter menopause earlier. Risk factors for developing depression in menopause include stress, body mass index, having had no live births, history of postpartum blues, family history of depression, history of sexual abuse and presence of hot flashes.
Women with depressive symptoms despite being on antidepressants were most likely to enter menopause early (2.7 times risk). Timing of menopause was not affected in women with history of depression (on or off antidepressants) without ongoing depressive symptoms. Dr. Susan Kornstein from Virginia Commonwealth University discussed treatment considerations. A particularly interesting point was that adding transdermal estrogen may enhance response to SSRI antidepressants. We at the Center also recommend stress reduction and relaxation techniques and various modalities of psychotherapy to improve mental health.
Hormones and Women’s Hearts – “Women are not little Men”
This plenary symposium emphasized the fact that “Women are not little Men” – Dr. Nieca Goldberg from New York University reviewed the different characteristics of heart disease in women as compared to men. Women younger than 50 suffer higher in-hospital mortality with their first heart attack and experience more heart failure compared to men. Women are also more likely to present with sudden cardiac death (without prior diagnosis of heart disease) compared to men. In fact, the type of plaque in the coronary arteries was different between the genders. Men tend to have more discrete plaques that are more readily visible on angiogram while women tend to have more diffuse plaque throughout the artery which may actually make the angiogram look “normal” (since there is no discrete point of narrowing). Women have more endothelial dysfunction and vasospasms.
Women may experience “prodromal symptoms” more than a month before their heart attack. These “prodromal symptoms” may include unusual fatigue, shortness of breath, anxiety, sleep disturbance and indigestion. Acute heart attack symptoms in women may include shortness of breath (most prominent symptom), fatigue, dizziness, weakness and cold sweats. Some women do present with the classical symptom of chest pressure/pain with or without radiation down the left arm/up to the jaw. Risk factors for heart disease in women include the classical one such as smoking, elevated LDL (“bad chol”), family history of premature heart disease (family members with heart disease under age 65), high blood pressure. But the most relevant risk factors in women are low HDL (“good chol”), elevated triglycerides, diabetes and abdominal obesity. Elevated CRP (C-reactive protein) is also a risk factor, whereas Lp(a) (a hereditary risk factor) infers significant risk in the presence of elevated LDL.
Dr. Howard Hodis from Keck School of Medicine reviewed the “duality of estrogen effects on natural history of atherosclerosis”. Let’s consider women initiating estrogen at different stages of their lives. In women less than 10 years past menopause and without cardiovascular risk factors (ie. healthier blood vessels, estrogen increases the production of nitric oxide which leads to relaxation of the blood vessels, a desirable effect. In women approximately 10-20 years past menopause, the benefits of estrogen on the vasculature are lost. Aging diseased blood vessels have reduced vascular responsiveness and lower expression of estrogen receptors. Even later, in women over 20 years past menopause, complex atherosclerotic plaques are already present. The addition of estrogen now increases MMP (matrix metalloproteinases) expression which leads to plaque instability and rupture, thereby increasing the risk of heart attack and stroke. This again supports the “critical time window” hypothesis and explains the findings from WHI in which women, aged 63 on average, were found to have increased risk of heart attack and stroke on estrogen and progestin therapy. Dr. JoAnn Manson from Harvard Medical School reported that when they re-analyzed the results from WHI according to age, in the estrogen-only arm there was actually a significant reduction in the risk of heart attack, coronary bypass or stent in women aged 50-59 at initiation of the study, whereas no benefit was seen in women aged 60-69 or 70-79. In the estrogen plus progestin arm, there was a trend to reduction of coronary heart disease risk in women aged 50-59 whereas harm was clearly seen in the group of women aged 70-79 at the initiation of the WHI study. Another interesting finding was that estrogen alone was associated with lower levels of coronary artery calcium by CT scanning.
Dr. Margery Gass from the University of Cincinnati and Dr. Manson helped put the risks of hormone therapy found by WHI into perspective. The change in absolute risk for women aged 50-59 for a number of conditions by hormone therapy is presented in the table below as number of cases per 10,000 women per year:
Estrogen + progestin therapy
|Venous thromboembolism (blood clots)||+11||+4|
|Coronary heart disease||+5||-10|
I would argue that increased chance of blood clots is the only irrefutable risk of oral estrogen / estrogen + progestin therapy. To further put this risk of venous thromboembolism into context, the increased risk seen in pregnancy is 5.9-19.4 cases per 10,000 women per year, whereas the increase in oral contraceptive use is 3-9 cases, similar to that associated with menopausal hormone use.
Ultimately it is our “perceived risk” that drives our individual decision regarding hormone therapy (or for any other choices in life, by the way). Each of us place different values on the different risks and benefits. Each individual woman therefore has to make her own informed choice and the role of the physician is to provide valid information regarding risks and benefits.
“Fitness for Survival”
The keynote address was presented by Dr. Pamela Peeke from the University of Maryland, author of the book “Fight Fat after Forty”. She introduced her new reality show which will air on Discovery Health Channel – participants are placed in hypothetical disaster situations in which they found out how unfit they really are. They were either unable to save a loved one or themselves in these hypothetical situations. Fortunately in TV reality shows it was possible to get a second chance – they underwent 4 weeks of lifestyle modification including nutrition and physical exercise training. It was truly gratifying to see how much improvement in their stamina and fitness they achieved in this short time. Dr. Peeke opined that survival is the most powerful motivator for us to improve fitness.
After our 20s, we start to lose muscle mass every year, leading to a reduction in basal metabolic rate. A 60 kcal drop in basal metabolic rate per day leads to a 6 pounds weight gain in a year! According to Dr. Peeke, an average American woman gains 30 pounds in weight while losing 15 pounds of muscle from the age of 20 to 50, which means she gains 45 pounds of fat!!! Many women attempt to lose weight by cutting calories, but this approach actually leads to weight loss that is predominantly muscle loss which does not yield metabolic or cardiovascular benefit. In fact, we have seen women who are “skinny fat”, eg. a 5 foot 8 woman weighing 120 pounds but has 33% body fat. Dr. Peeke contends that body composition is much more important than scale weight, which I agree with – our First Line Therapy Program is a low glycemic Mediterranean eating plan that focuses on improvement of body composition, and thereby reducing diabetes and heart disease risk. Instead of just looking at the scale, we use body composition testing to measure progress. In order to maximize the improvement in body composition, we recommend weight resistance exercises (eg. light weights, yoga, pilates) balancing cardio workouts. Increasing muscle mass means burning more calories even at rest as our basal metabolic rate is largely determined by our muscle mass.
An abstract presented by scientists from University of Michigan, Ann Arbor found that weight loss and health-related goals were NOT effective for increasing women’s participation in physical activity. However, goals of improving sense of wellbeing and reducing stress were much more likely to lead to sustained physical activity. This is a good reminder to us that rather than specific goals such as appearance or lowering cholesterol, we should put whole-person optimal health and wellbeing as our goal for our lifestyle modifications.