Emerging Trends

Vision: Age-Related Macular Degeneration

Deterioration in visual acuity and dryness were the 2 most common complaints of the 19 reported. Ninety-eight women underwent ophthalmic examination and received cyclical HRT for 3 months. Most of the women who were followed reported substantial improvement or complete freedom from their ocular complaints by the end of 3 months. Moreover, physician examination provided objective evidence of improvement in 2 parameters: increased lacrimal fluid, and improved convergence and fusion (which is indicative of improved visual acuity).

Studies are uncovering other possible benefits from estrogen replacement therapy. For instance, age-related macular degeneration (AMD) may be reduced by estrogen administration.(68) This disease is the leading cause of legal blindness in the United States, accounting for as many as 60% of all new cases. Early-stage AMD is common in the population, and patients are usually asymptomatic. About 17% of the population between the ages of 43 and 86 years have this type of AMD. This figure rises to 35% when the >75 population is isolated.

The prevalence of late-stage, or exudative, disease increases after the age of 75 years (Figure 9), and this increase is more significant in women than in men. Late-stage disease, both the wet and dry types, affect 7% of the elderly population.(69) It is the late-stage disease that most often leads to blindness. The pathogenesis of the disease is poorly understood, although there is a high association between AMD and smoking. There is no medical treatment, and surgical treatment in the form of photocoagulation is effective in only a small percentage of patients with the wet type of the disease.

Figure 9

There is some evidence that there is an association between menopause and AMD. In the Rotterdam study, women with a younger age at menopause had a 90% increased risk of exhibiting signs of late AMD compared to those whose age at menopause was older.(70) The data in Table 7 are from a large case-controlled study of end-stage disease, and these data suggest that HRT reduces the risk of developing AMD.(68) Another study also suggested that ERT/HRT produces a very small reduction that is not statistically significant for early and late stages of AMD.(71) There was a 1% to 4% reduction of AMD per year of ERT/HRT depending upon the severity level of AMD.

Table 7

Parkinson's Disease

Given estrogen's effect on the CNS, research efforts are just now beginning to investigate Parkinson's disease (PD) and HRT. PD is a neurodegenerative disorder affecting the dopamine-producing cells of a specific region of the brain: the substantia nigra (Table 8).(72-75) PD is characterized by 4 cardinal features: tremor at rest, rigidity, bradykinesia or slowness of movement, and postural instability. Patients may have some or all of these features. Over time, there is gradual progression of the motor symptoms of PD. In addition, long-term complications of treatment, which may include motor fluctuations, dyskinesia, psychosis, and dementia, develop in the majority of patients.

Table 8

The mean age of onset of PD is 58 to 62 years, and the incidence of this disease increases with age (Figure 10).(76) Most epidemiological studies reveal a prepond-erance of PD cases in men; specifically, studies suggest a 60% to 40% split between men and women.

Figure 10

PD becomes clinically evident only when the majority of substantia nigra neurons are lost. It is not known precisely when this process begins, although many believe that neurodegeneration starts 10 or more years prior to the emergence of symptoms. For women, this means neurodegeneration often begins premenopausally, at the time when women might reasonably consider beginning HRT for its benefits. Thus, attention has recently focused anew on how estrogen affects PD.

Case studies from the last 20 years that examined the effect of estrogen on PD and other dopamine-related disorders are contradictory. They report mixed effects for estrogen, but the abundant basic science literature reveals numerous mechanisms supporting a positive effect of estrogen on dopamine neurotransmission.(77-81) Estrogen may work directly as a neuroprotective agent on the dopamine neurons. It may also increase sensitivity to dopamine as well as decrease dopamine reuptake.

Several small studies suggest that estrogen has a direct beneficial effect on the pharmacokinetics of levodopa, which is the mainstay of treatment for PD.(82-86)

Clinically, estrogen administration might prove eventually to have a beneficial effect on levodopa metabolism, which could increase the efficacy of levodopa and reduce the dosage of levodopa needed.

One recent study found that estrogen administration was associated with less severe Parkinson's symptoms.(87) It included only women who had symptoms of presumed PD for <5 years and who were not yet taking levodopa at the time of their first visit. The effect of estrogen on disease severity was assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). Thirty-four of the women had used estrogen at some time and 104 had never received estrogen. The investigators found a positive and significant association between estrogen use and lower symptom severity in women with early PD (Figure 11).

Figure 11

About 40% of PD patients develop dementia, and the majority of patients develop some degree of cognitive dysfunction. In a clinical study using a battery of cognitive tests to evaluate female patients with PD, estrogen had an impact on cognitive function. All of the women, regardless of ERT use, had similar ability to learn new verbal material, but ERT use was associated with better retention of that learned material.(88) Another study found that estrogen reduced the development of dementia among women with Parkinson's disease.(89) Although the data on estrogen and PD are preliminary, there is sufficient suggestion of a beneficial effect to warrant further study.

Diabetes

Another area in which preliminary evidence is just beginning to emerge is the effect of estrogen on diabetes. As the population ages, the economic and sociological impact of diabetes, particularly type 2 diabetes, will increase dramatically. Approximately half of all diabetes cases occur in people over the age of 55.(90) And by the year 2015, 45% of all women in the United States will be 45 years of age or older.(91) The makeup of the US diabetes population emphasizes this point: 5% to 10% have type 1; 90% to 95% have type 2; and 2% to 5% have gestational diabetes. Almost 6% of the US population is affected by diabetes, although roughly 1/3 of those with the disease remain undiagnosed.(90) Current estimates of the total yearly cost of diabetes, both direct and indirect, are $98 billion.(90) Moreover, the complications of diabetes are significant (Table 9).

Table 9

One of the most devastating consequences of diabetes is its contribution to cardiovascular disease. As many as 75% of deaths in individuals with diabetes are caused by heart disease or stroke.(92) The Nurses' Health Study revealed that women with diabetes have a 5-fold higher risk of coronary heart disease than do nondiabetic women.(92,93) Furthermore, diabetes somehow negates the protective effect that being female usually has on the risk of developing heart disease.(91,92,94)

The effect of diabetes on cardiovascular mortality is dramatically illustrated in this 24-year follow-up of a large cohort of patients (Figure 12). The study included diabetic men and women who were diagnosed between the ages of 35 and 64 years and who came to the Joslin Clinic soon after diagnosis. They were compared to a group of similarly aged nondiabetic participants in the Framingham study.(95) The increased coronary artery disease (CAD) mortality among diabetic patients, which is already evident in the first 3 years of observation, increased significantly as time progressed.

Figure 12

Recent investigations have provided a wealth of information about the effects of hormone replacement therapy on disease prevention in predominantly healthy women. However, because women with diabetes have been systematically excluded from the majority of early prospective trials of ERT/HRT, scant information is available about the effects of estrogen in this population.

One study has found a decreased risk of myocardial infarction (MI) in diabetic women currently taking HRT. Case subjects were all postmenopausal women with treated diabetes who had had a fatal or nonfatal MI.(96) Controls were treated diabetic postmenopausal women without prior MI. History of ERT/HRT use was obtained from computerized pharmacy records. The relative risk of MI for current estrogen users was 0.51 (0.22-1.15), which represents a 49% reduction. The relative risk for MI declined with each additional year of estrogen use. But such protection was completely lost among women who had discontinued estrogen.

Studies are now beginning to look at how estrogen affects the management of diabetes itself. A prospective trial of 18 women evaluated the effect of 8 weeks of estrogen (conjugated equine estrogen [CEE] 0.625 mg) vs 8 weeks of placebo in the same group separated by a 4-week washout period.(97) The investigators found that estrogen produced better control, both in fasting glucose and glycated hemoglobin. The same trial also measured lipoproteins. ERT produced significant decreases in cholesterol and LDL and a significant increase in HDL. The precise mechanisms by which estrogen might improve control of diabetes need further investigation, but estrogen therapy may improve insulin resistance and may decrease the production of glucose in the liver.

Osteoarthritis

Finally, because of the effect of estrogen on bone, one study examined estrogen's impact on osteoarthritis. In the study in Figure 13, radiographs of the pelvis were obtained for 4366 women aged greater than or equal to 65 years.(98) Overall, the current use of estrogen was associated with less risk of osteoarthritis. The greatest reduction was seen in women who had used estrogen longer than 10 years.

Figure 13