Early
1990s
Multiple epidemiological studies show a 40-50 percent reduction in cardiovascular disease in women using postmenopausal estrogens (31).

Studies demonstrate the presence of multiple estrogenic components in Premarin (32).

Tamoxifen is the first selective estrogen receptor modulator (SERM) introduced for use in the treatment of women with breast cancer (33).

An increasing interest in alternative medicine develops in the United States even though controlled clinical studies do not show clinical improvements with most of these alternatives. For example, dong quai and placebo (no hormone) have a similar effect on menopausal symptom (34). Use of phytoestrogens (estrogens derived from plants) for the treatment of menopausal symptoms increases (35).

Oral contraceptives contain one-fourth the estrogen and one-tenth the progestin dose of earlier pills.

The Women's Health Initiative (WHI) clinical trial and observational study, sponsored by the National Institutes of Health (NIH), is initiated with a planned completion date of 2007. More than 161,000 postmenopausal women, ranging in age from 50-79, are enrolled at one of 40 WHI clinical centers nationwide, with more than 27,000 randomized to receive hormone therapy (HT). The objective of the clinical trial is to evaluate the effects of postmenopausal estrogen use, dietary patterns and calcium/vitamin D supplements on overall mortality, cardiovascular disease, breast cancer, colon cancer, osteoporosis and other disease processes.

Mid
1990s
Studies suggest an increased incidence of endometrial cancer with long-term tamoxifen use (36).

Studies suggest postmenopausal estrogen use may play a role in the prevention of Alzheimer's disease, age-related eye disease, colon cancer, and tooth loss (37, 38, 39, 40).

Initiation of the Women's Health, Osteoporosis, Progestin, Estrogen Study (Women's HOPE Study) to evaluate the effects of low-dose HT on menopausal symptoms and osteoporosis. The Women's HOPE Study is the first large trial to evaluate the effects of low-dose therapy on menopausal symptoms, amenorrhea, osteoporosis and metabolism.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial shows that Premarin 0.625 mg, with or without a progestin, results in increases in bone mineral density in both the hip and spine (41).

Late
1990s
Studies suggest that estrogens may protect women against diabetes and Parkinson's disease (42, 43).

Estrogen receptors are identified in multiple organ systems.
Multiple mechanisms to explain the possible beneficial effects of estrogens in organ systems, such as the cardiovascular system, begin to be delineated.

A second estrogen receptor is discovered. The two estrogen receptors (alpha and beta) are distributed differently throughout the body.

New clinical trials begin in the hopes of identifying the ideal SERM. Raloxifene, a second generation SERM, is introduced for the prevention of osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) and the Raloxifene Use for The Heart (RUTH) trials are initiated to determine the effect of raloxifene on bone health, as well as the incidence of breast cancer and cardiovascular disease (44, 45, 46).

In addition to providing effective contraception, low-dose oral contraceptives are shown to reduce menopausal symptoms by half and improve quality of life for perimenopausal women (47).

1997
A re-analysis of the data from 51 epidemiological studies suggests an increased risk of breast cancer with postmenopausal hormone use (48). The debate regarding the effect of estrogens continues, awaiting results from prospective randomized trials.

*P=.009, for trend-time analysis
Hulley et al. JAMA. 1998;280:605

1998
The Heart Estrogen/Progestin Replacement Study (HERS) was unable to demonstrate a cardiovascular benefit of HT in postmenopausal women with established coronary artery disease (49). Women given HT show an increased risk of a second cardiovascular event during the first year compared to women given placebo. A time-trend analysis shows improvement with HT over time in subsequent years but no overall benefit.