There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

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The complex role of estrogens in inflammation

There is now a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in proinflammatory cytokines. The cytokines that have obtained the most attention are IL-1, IL-6, and TNF-alpha. The exact mechanisms by which estrogen interferes with cytokine activity are still incompletely known but may potentially include interactions of the ER with other transcription factors, modulation of nitric oxide activity, antioxidative effects, plasma membrane actions, and changes in immune cell function. Experimental and clinical studies strongly support a link between the increased state of proinflammatory cytokine activity and postmenopausal bone loss. Preliminary evidence suggests that these changes also might be relevant to vascular homeostasis and the development of atherosclerosis. Better knowledge of the mechanisms and the time course of these interactions may open new avenues for the prevention and treatment of some of the most prevalent and important disorders in postmenopausal women.

Changes in proinflammatory cytokine activity after menopause.

Estrogen deficiency induced bone loss is associated with increased bone turnover in rats and humans. The respective roles of increased bone turnover and altered balance between bone formation and bone resorption in mediating estrogen deficiency-induced cancellous bone loss was investigated in ovariectomized rats. Ovariectomy resulted in increased bone turnover in the distal femur. However, cancellous bone was preferentially lost in the metaphysis, a site that normally experiences low strain energy. No bone loss was observed in the epiphysis, a site experiencing higher strain energy. The role of mechanical strain in maintaining bone balance was investigated by altering the strain history. Mechanical strain was increased and decreased in long bones of ovariectomized rats by treadmill exercise and functional unloading, respectively. Functional unloading was achieved during orbital spaceflight and following unilateral sciatic neurotomy. Increasing mechanical loading reduced bone loss in the metaphysis. In contrast, decreasing loading accentuated bone loss in the metaphysis and resulted in bone loss in the epiphysis. Finally, administration of estrogen to ovariectomized rats reduced bone loss in the unloaded and prevented loss in the loaded limb following unilateral sciatic neurotomy in part by reducing indices of bone turnover. These results suggest that estrogen regulates the rate of bone turnover, but the overall balance between bone formation and bone resorption is influenced by prevailing levels of mechanical strain.

https://www.pnas.org/content/pnas/94/8/4199.full.pdf

Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain

In vivo, human parathyroid hormone fragment (hPTH 1-34) transiently stimulates immediate early response gene expression, but not proliferation, in trabecular bone cells of young rats.

Analysis of estrogens in serum and plasma from postmenopausal women: past present, and future.

The Effect of Long-Term Ovarian Hormone Deficiency on Transforming Growth Factor β and Bone Matrix Protein mRNA Expression in Rat Femora

Recent data indicate that the catechol estrogen, 2-hydroxyestrone (2-OHE 1 ), has no effect on any target tissue including bone, whereas 16-hydroxyestrone (16-OHE 1 ) exerts tissue-selective estrogen agonist activity. The effect of the catechol estrogen, 4hydroxyestrone (4-OHE 1 ), putatively associated with tumorigenesis, has not been studied in the skeleton. The purpose of this study was to assess the effect of 4-OHE 1 on tibia, uterine and mammary gland histology and blood cholesterol in ovariectomized (OVX’d) growing rats. Ten-week-old female Sprague–Dawley rats were injected subcutaneously with 200 µg/kg BW per day with 4-OHE1 ,1 7-estradiol (E2) or vehicle for three weeks. OVX resulted in uterine atrophy, increased body weight, radial bone growth and cancellous bone turnover, and hypercholesterolemia. E2 prevented these changes with the expected exception that the subcutaneous infusion of this high dose of estrogen did not prevent the hypercholesterolemia. 4-OHE1 prevented the increase in blood cholesterol and the increase in body weight. 4-OHE 1 appeared to have partial estrogen activity in the uterus; uterine weight and epithelial cell height were significantly greater than the OVX rats but significantly less (twofold) than the E 2 animals. Analysis of variance indicated that 4-OHE 1 slightly decreased the periosteal mineral apposition rate (P<0·05) compared with vehicletreated rats but had no effect on double-labeled perimeter or bone formation rate. Similarly, 4-OHE 1 was a partial estrogen agonist on cancellous bone turnover. The data suggest that the catechol estrogen, 4-OHE1, unlike 2-OHE1, has estrogen activity. Furthermore, the profile of activity differs from that of 16-OHE1. Our results suggest that estrogen metabolites may selectively influence estrogen-target tissues and, concomitantly, modulate estrogen-associated disease risk.

/pdf/the-catechol-estrogen-4-hydroxyestrone-has-tissue-specific-z5eoxgfwar.pdf

G L. Evans

Papers

The Effect of Long-Term Ovarian Hormone Deficiency on Transforming Growth Factor β and Bone Matrix Protein mRNA Expression in Rat Femora

The catechol estrogen, 4-hydroxyestrone, has tissue-specific estrogen actions.