Estrogen deficiency

DRAPER c R, DICK I M and PRINCE R L (1999) The effect of estrogen deficiency on calcium balance in mature rats. Calcif Tissue Int 64, 325-8. 

ISHIMI Y, MIYAURA 0, OHMURA M, ONOE Y, SATO T, UCHIYAMA Y, ITO M, WANG X, SUDA T and IKEGAMI s (1999) Selective effects of genistein, a soybean isoflavone, on B-lymphopoiesis and bone loss caused by estrogen deficiency. Endocrinol 140, 1893-1900. 

RIGGS B L, KHOSLA s and MELTON L J, 111 (1998) A Unitary model for involutional osteoporosis estrogen deficiency causes both type 1 and type 11 osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Min Res 13, 16 i-l i. 

Vaginally-administered estrogen plays only a modest role in managing stress urinary incontinence (urethral underactivity), unless it is accompanied by local signs of estrogen deficiency (e.g., atrophic urethritis or vaginitis). 

Pelvic exam (females) (look for evidence of prolapse of bladder, small bowel, rectum, or uterus, or estrogen deficiency)... 

Other symptoms, including mood swings, depression, insomnia, migraine, formication, arthralgia, myalgia, and urinary frequency, are attributed to menopause, but the relationship between these symptoms and estrogen deficiency is controversial. 

Women with secondary amenorrhea (i.e., cessation of menses in a woman who was previously menstruating for 6 months or more) who have been estrogen deficient for 12 months or longer should also receive low-dose estrogen initially, but the dose can be increased up to maintenance levels... 

The proposed model to explain OCS is schematized in Fig. 7.2. Several agents, induced or not for estrogen deficiency, stimulate the expression of RANKL on stromal/OB cells. The binding of RANKL with its receptor RANK on osteoclastic precursors, together with M-CSF, is a necessary and sufficient condition to carry out all the steps in the formation and differentiation of the osteoclasts. Undoubtedly all this is much more complex than what is described here since at least 24 genes that positively and negatively regulate OCS have been described (Boyle et al. 2003). 

Fig. 7.3. Osteoclastogenesis after estrogen deficiency. Estrogen deprivation leads to an increase in the synthesis of RANKL for stromal/OB cells of the BM. This increase in the expression of RANKL leads to an increase in OCS. Estrogen deficiency also induces the synthesis and secretion of cytokines, such as IL-6 and M-CSF, that increase the number of preosteoclasts in the BM, and thus increases OCS. Nonetheless, certain cells of the immune system, such as monocytes and T-cells, intervene in the process when the supply of estrogens fails. These cells secrete IL-1 and TNF-a that are powerful inductors of OCS. When estrogens or agonists of estrogen receptors like raloxifene are administered, the synthesis and secretion of many of the mentioned cytokines diminish and the synthesis and liberation of OPG and TGF-/S are stimulated. These molecules inhibit OCS by inhibiting the RANKL/RANK signal pathway and by promoting osteoclast apoptosis...

If the RANKL/OPG system is a final effector on the biology of osteoclasts, then this system should be the basis for the antiresorptive effects of estrogen. Indeed, estrogen stimulates OPG synthesis for osteoblastic cells (Hofbauer et al. 1999), estrogen deficiency induced by OVX results in a decrease in OPG and increased RANKL production, an action that is prevented by estradiol administration, and OPG administration prevents bone loss induced by OVX (Simonet et al. 1997 Hofbauer et al. 2000 Hofbauer 1999). In addition, estrogen can suppress RANKL and M-CSF-induced differentiation of myelomonocytic precursors into multinucleated TRAP+ osteoclasts through an ER-dependent mechanism that does not require mediation by stromal cells (Shevde et al. 2000). Finally, treatment with estradiol inhibits the response of osteoclast precursors to the action of RANKL (Srivastava et al. 2001). 

Jilka RL (1998) Cytokines, bone remodeling, and estrogen deficiency a 1998 update. Bone 23 75-81... 

Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, Pacifici R (2000) Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106 1229-1237... 

Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, Pacifici R (2001) Up-regulation of TNF-producing T cells in the bone marrow a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc Nad Acad Sci USA 98 13960-13965... 

Ammann P, Rizzoli R, Bonjour JP, Bourrin S, Meyer JM, Vassalli P, Garcia I (1997) Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. J Clin Invest 99 1699-1703... 

Kimble RB, Srivastava S, Ross FP, Matayoshi A, Pacifici R (1996) Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-land tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production. J Biol Chem 271 28890-28897... 

A more long-term rabbit model of estrogen deficiency has also been recently described in which adult OVX rabbits (7 months) were treated with the Cat K inhibitor L-006235 (12) at 0,2,10 mg/kg, or ALN (0.125 mg/kg, 3x/wk) for 27 weeks. OVX resulted in an 11.5% vertebral bone loss compared to sham-operated controls. Both the high dose of L-006235 and ALN completely prevented this bone loss, whereas the low dose of L-006235 produced a partial response [19]. 

Osteoporosis (alendronate) Consider causes other than estrogen deficiency and aging consider glucocorticoid use. 

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