Bench to Bedside: Clinical Studies

II. Clinical Studies

Cardiovascular Health and Cognition: Perspectives on Using the Primate as a Model for Human Research—Dr. Thomas B. Clarkson

Dr. Clarkson's presentation addressed the following:

1. Use of nonhuman primates to elucidate the clinical implications of estrogen effects on early atherosclerosis versus complicated plaques. 
2. Use of nonhuman primates to investigate the pathobiologic mechanisms whereby postmenopausal estrogen treatment can provoke plaque instability in the later stages of coronary artery atherosclerosis progression. 
3. Use of mgfionkey models to explore the cardiovascular health and cognition across the menopausal transition (premenopausal—perimenopausal—menopausal—postmenopausal).
4. Overview of the Kronos Early Estrogen Prevention Study (KEEPS) study.

Specific points included:

• Coronary artery disease can progress from age 15 on.
• Hormone therapy has a beneficial effect through ages 35–55, but no benefit after age 55.
• Women with CAD, on average, have lower levels of E2.
• For surgically induced menopause in monkeys, estrogen given immediately prevents CAD, while estrogen given late on (greater than 5–6 years) does not.
• KEEPS is testing this in women.
• Estrogen: "good" early, "bad" late.

Consequences of Surgical Menopause on Cognition and Mood—Dr. Barbara Sherwin

Dr. Sherwin's presentation highlighted the following:

1. The drastic nature of the endocrine changes when surgery is undertaken in premenopausal women and whether the high incidence of symptoms is related to the abruptness of the hormonal changes.
2. Surgical menopause involves changes in androgen and in estrogen concentrations.
3. The possibility that surgically menopausal women—who are generally younger than naturally menopausal women when they are deprived of ovarian function—may be rendered more vulnerable to diseases of aging.
4. Possible adverse consequences of premenopausal ovarian ablation also would apply to treatment of women with nonestrogen sensitive cancers whose ovarian function is compromised by radiation and/or chemotherapy treatments.
5. The relationship between mood changes and cognition in women.

Specific points included:

• There are 600,000 hysterectomies and 300,000 ovariectomies per year in the United States.
• There are 10 million surgically menopausal women in the United States.
• Estradiol drops most between 50 and 52 and levels off at approximately age 57 at about 60–80 pmol/l.
• The ovary produces 25 percent of androsterone, 10 percent of dihydroepiandrosterone (DHEA); therefore, the levels of testosterone (T) are about half in ovariectomized (ovx) women.
• When ovx women are replaced with estrogen alone, sex hormone binding globulin (SHBG) levels rise, allowing more of their diminished levels of endogenous T to be bound and biologically inactivated.
• There is a beneficial effect of estrogen on verbal—but not visual—memory when replaced.
• Beck scores decreased on E compared to an increase on P.

CNS Effects of Hypogonadism and Estrogen Therapy in Humans—Dr. Peter Schmidt

Dr. Schmidt's presentation addressed the following:

1. Efficacy of short-term estradiol therapy in perimenopause-related depression (but not postmenopause).
2. Evidence of an increased risk for the onset of depression within 24 months after the last menstrual period.
3. Effects of GnRH agonist-induced ovarian suppression with and without estradiol and progesterone replacement on measures of mood, cognitive performance (e.g., verbal memory), cognition-activated regional cerebral blood flow (positive electron tomography [PET]) and BOLD functional magnetic resonance imaging (fMRI) studies.  

Specific points included:

• Estradiol decreases depression in perimenopausal, but not postmenopausal, women.
• Although the majority of women do not develop a depression during the menopausal transition, prospective longitudinal studies identified perimenopause as a time during which some women may be at an increased risk for the development of a depressive illness.
• Hypogonadism and estradiol or progesterone treatment will differentially alter the pattern of cognition-activated regional cerebral blood flow in the prefrontal cortex of the brain (as measured by O 15 PET).

The Differential Effects of Estrogen on Mood and Cognition in Peri- and Postmenopausal Women—Dr. Neill Epperson

Dr. Epperson's presentation highlighted the following:

1. The role of serotonin and aging in menopausal women.
2. The impact of estrogen on serotonergic function.
3. The serotonin/estrogen interplay in mediating mood and cognition.
4. The impact of tryptophan depletion on mood and cognition in menopausal women pre- and postestrogen therapy.

Specific points included:

The tryptophan depletion paradigm can be used to study the effects of reduced brain serotonin on cognition and mood in humans:

• Tryptophan depletion results in decreased performance on the delayed paragraph recall and the paired associates subtasks of the Wechsler Memory Scale-Revised in both peri- and postmenopausal women.
• Estrogen improves performance on the delayed paragraph recall and the paired associates subtasks.

In summary, estrogen appears to "protect" menopausal women from the detrimental effects that a reduction in brain serotonin has on certain aspects of cognitive function.    

Estrogen or No Estrogen: Long-Term Followup—Dr. Natalie Rasgon

Dr. Rasgon's presentation addressed the following:

1. Brain metabolism in hypoestrogenic (postmenopausal) women with major depressive disorder.
2. Brain metabolism in women with hypothyroidism.
3. Brain metabolism in persons with familial and/or genetic risk for Alzheimer's disease.

Specific points included:

• PET imaging.
• No differences between estrogen users and nonusers in memory at baseline.
• For more than 2 years, there was a slight increase in posterior cingulate metabolism when estrogen was not seen in nonestrogen users.

Low-Dose Estrogen, fMRI, and Cognitive Function—Dr. Vincent P. Clark

Dr. Clark's study concluded the following:

• Low-dose 17 B -estradiol does not significantly alter behavioral responses in a simple reaction time task.
• Brain activation patterns in older women are consistent with findings in younger women.
• fMRI responses in posterior parietal and lateral occpital-temporal brain areas were reduced with low-dose 17 B -estradiol relative to placebo, suggesting greater efficiency of stimulus processing.
• However, because fMRI is an indirect measure of neural activity, these fMRI results may be because of the neural or hemodynamic effects of 17 B -estradiol.

Specific points included:

• Women on or off low-dose E + P for 3 years (N=16 with fMRI) were studied. There was no change in reaction time, but there were some changes in fMRI BOLD signal.

Cognitive and Brain Aging: Using Imaging To Distinguish Potential Risks and Benefits of Estrogen—Dr. Susan Resnick

Dr. Resnick's presentation highlighted the following:

1. BLSA studies of hormone therapy and cognition.
2. Women's Health Initiative Study of Cognitive Aging (WHISCA) findings on specific cognitive functions from the E + P subtrial of the WHI.
3. Differential effects of HT on specific cognitive functions—competing risks and benefits.
4. Imaging techniques to distinguish potential risks and benefits.

Specific points included:

• BLSA observational studies indicate better verbal and figural memory in women using hormone therapy compared with "never" users.
• The WHISCA study investigated the effects of hormone therapy on rates of changeover time in specific cognitive functions.
• WHISCA E + P subtrial: about 700/group, well balanced with respect to demographic characteristics and 3MS at WHI and WHISCA baselines.
• Randomized and treated for about 3 years before first assessment.
• One-year followup for 92 percent; 43 percent had 2 years on treatment.
• At baseline after 3 years treatment, there were no robust effects.
• For change rate over time, E + P women are worse on some aspects of memory, but better on others.
• WHISCA CEE alone analysis is underway.

Vascular Disease in the Brain: An Important Cause of Dementia?—Dr. Lew Kuller

Dr. Kuller's presentation outlined the following:

1. Very high prevalence of vascular disease in the brain (i.e., high white matter grade and infarcts).
2. Vascular disease in the brain was strongly associated with dementia.
3. Without MRI, it is impossible to measure "vascular disease in the brain" and dementia type. Much of dementia is likely a mixture of Alzheimer's disease-type pathway and vascular disease.
4. Estrogen therapy increases the risk of stroke. Risk of dementia may be a function of vascular disease in the brain. If so, it might be necessary to develop preventive strategies for women who were on estrogen or estrogen and progesterone therapy.

Specific points included:

• The cardiovascular health study found that about 20–25 percent of men and women with no prior history of stroke have subclinical infarcts (N=~3,000).
• Of 500 persons, about 50 percent had AD, 35 were MIX, and 15 percent had vascular dementia.

Why Don't Estrogens Work?

• Poor lipid lowering
• Increase of thrombosis
• Differential effects (i.e., works in the young, not old)
• Metabolites of estrogens in blood
• Weight gain "wipes out" the benefit of HT

Discussion—Clinical Studies

• Tasks that can differentiate hippocampus from the frontal cortex are needed (presently available: delayed matching and nonmatching to sample).
• There is a need for lifestyle change analysis.