Menopause and hormone replacement therapy: effects on the immune system, arthritis and bone

Menopause is, among other things, associated with increased risk of bone loss and development of rheumatoid arthritis (RA). Numerous postmenopausal women in the Western world have replaced the endogenous estrogen by treatment with hormone replacement therapy (HRT) (i.e. estrogen + progestin) or estrogen replacement therapy (ERT) (i.e. estrogen alone). Until recently HRT was also regarded as preventive of cardiovascular disease, and possibly even dementia. However, recent findings in large placebo-controlled studies of long-term HRT and ERT in healthy postmenopausal women demonstrated an increased risk of coronary events, stroke, breast cancer and pulmonary embolism among the HRT-treated women. Consequently, today HRT is only recommended for 3–6 months in women with severe menopausal symptoms.

Is there any evidence that HRT has beneficial effects on established RA? We recently completed a 2-year controlled, randomized and prospective trial comparing calcium/vitamin D₃ + HRT and calcium/vitamin D₃ alone in patients with long-lasting RA. The outcome clearly showed that the HRT-treated patients responded with a significant decrease in Disease Activity Score 28 and laboratory signs of inflammation (sedimentation rate and hemoglobin), an increase in bone mineral density and less progression of radiographic joint destruction compared with controls [1]. Unfortunately, we do not know how HRT affects the increased risk for vascular disease in RA.

How could we develop a 'safe' HRT with preserved bone protective and anti-arthritic properties? It is an absolute necessity to increase our understanding of how estrogen exerts its effects in different biological compartments. We therefore conducted several studies in estrogen receptor (ER) knockout mice lacking one or both of ER-α and ER-β. In summary, these experiments show that ER-α is the dominant receptor for estrogen-mediated effects on immune organ development, T and B lymphopoiesis and inflammation, and that ER-β seems to play a regulatory role [2, 3].

Another approach was to analyze the immune-modulating, antiinflammatory and anti-arthritic properties of a selective estrogen receptor modulator, raloxifene [4], and the synthetic compound 4-estren-3α, 17β-diol (estren) [5]. Data from recent, as yet unpublished, experiments will be presented and discussed.

In conclusion, although certain side-effects of conventional HRT have been identified, there is good hope of finding HRT that reproduces only the beneficial effects of estrogen on bone and arthritis.