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Estrogen Deficiency (estrogen + deficiency)

Distribution by Scientific Domains

Medical Sciences	91%
Life Sciences	8%

Selected Abstracts

Mice Lacking the Plasminogen Activator Inhibitor 1 Are Protected from Trabecular Bone Loss Induced by Estrogen Deficiency

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2000
E. Daci
Abstract Bone turnover requires the interaction of several proteases during the resorption phase. Indirect evidence suggests that the plasminogen activator/plasmin pathway is involved in bone resorption and turnover, and recently we have shown that this cascade plays a role in the degradation of nonmineralized bone matrix in vitro. To elucidate the role of the plasminogen activator inhibitor 1 (PAI-1) in bone turnover in vivo, bone metabolism was analyzed in mice deficient in the expression of PAI-1 gene (PAI-1,/,) at baseline (8-week-old mice) and 4 weeks after ovariectomy (OVX) or sham operation (Sham) and compared with wild-type (WT) mice. PAI-1 inactivation was without any effect on bone metabolism at baseline or in Sham mice. However, significant differences were observed in the response of WT and PAI-1,/, mice to ovariectomy. The OVX WT mice showed, as expected, decreased trabecular bone volume (BV/TV) and increased osteoid surface (OS/BS) and bone formation rate (BFR), as assessed by histomorphometric analysis of the proximal tibial metaphysis. In contrast, no significant change in any of the histomorphometric variables studied was detected in PAI-1,/, mice after ovariectomy. As a result, the OVX PAI-1,/, had a significantly higher BV/TV, lower OS/BS, lower mineral apposition rate (MAR) and BFR when compared with the OVX WT mice. However, a comparable decrease in the cortical thickness was observed in OVX PAI-1,/, and WT mice. In addition, the cortical mineral content and density assessed in the distal femoral metaphysis by peripheral quantitative computed tomography (pQCT), decreased significantly after ovariectomy, without difference between PAI-1,/, mice and WT mice. In conclusion, basal bone turnover and bone mass are only minimally affected by PAI-1 inactivation. In conditions of estrogen deficiency, PAI-1 inactivation protects against trabecular bone loss but does not affect cortical bone loss, suggesting a site-specific role for PAI-1 in bone turnover. [source]

Prostaglandin E2 Induces Expression of Receptor Activator of Nuclear Factor,,B Ligand/Osteoprotegrin Ligand on Pre-B Cells: Implications for Accelerated Osteoclastogenesis in Estrogen Deficiency

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2000
Masahiro Kanematsu
Abstract Estrogen deficiency causes bone loss as a result of accelerated osteoclastic bone resorption. It also has been reported that estrogen deficiency is associated with an increase in the number of pre-B cells in mouse bone marrow. The present study was undertaken to clarify the role of altered B lymphopoiesis and of the receptor activator of nuclear factor-,B ligand (RANKL), a key molecule in osteoclastogenesis, in the bone loss associated with estrogen deficiency. In the presence of prostaglandin E2 (PGE2), the activity to form tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells was significantly greater in bone marrow cells derived from ovariectomized (OVX) mice than in those from sham-operated mice. Northern blot analysis revealed that PGE2 increased the amount of RANKL messenger RNA (mRNA) in bone marrow cells, not only adherent stromal cells but nonadherent hematopoietic cells; among the latter, RANKL mRNA was more abundant in OVX mice than in sham-operated mice and was localized predominantly in B220+ cells. Flow cytometry revealed that most B220+ cells in bone marrow were RANKL positive and that the percentage of RANKL-positive, B220low cells was higher in bone marrow from OVX mice than in that from sham-operated mice. The increase in the expression of RANKL and the percentage of these cells in OVX mice was abolished by the administration of indomethacin in vivo. PGE2 also markedly increased both the level of RANKL mRNA and cell surface expression of RANKL protein in the mouse pre-B cell line 70Z/3. Finally, osteoclastogenic response to PGE2 was reduced markedly by prior depletion of B220+ cells, and it was restored by adding back B220+ cells. Taken together with stimulated cyclo-oxygenase (COX)-2 activity by tumor necrosis factor , (TNF-,) and interleukin-1 (IL-1) in estrogen deficiency, these results suggest that an increase in the number of B220+ cells in bone marrow may play an important role in accelerated bone resorption in estrogen deficiency because B220+ cells exhibit RANKL on the cell surface in the presence of PGE2, thereby leading to accelerated osteoclastogenesis. [source]

Protein Undernutrition-Induced Bone Loss Is Associated with Decreased IGF-I Levels and Estrogen Deficiency

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2000
Patrick Ammann M.D.
Abstract Protein undernutrition is a known factor in the pathogenesis of osteoporotic fracture in the elderly, but the mechanisms of bone loss resulting from this deficiency are still poorly understood. We investigated the effects of four isocaloric diets with varying levels of protein content (15, 7.5, 5, and 2.5% casein) on areal bone mineral density (BMD), bone ultimate strength, histomorphometry, biochemical markers of bone remodeling, plasma IGF-I, and sex hormone status in adult female rats. After 16 weeks on a 2.5% casein diet, BMD was significantly decreased at skeletal sites containing trabecular or cortical bone. Plasma IGF-I was decreased by 29,34% and no estrus sign in vaginal smear was observed. To investigate the roles of estrogen deficiency and protein undernutrition, the same protocol was used in ovariectomized (OVX) or sham-operated (SHAM) rats, pair-fed isocaloric diets containing either 15 or 2.5% casein. Trabecular BMD was decreased by either manipulation, with effects appearing to be additive. Cortical BMD was decreased only in rats on a low-protein diet. This was accompanied by an increased urinary deoxypyridinoline excretion without any change in osteocalcin levels, suggesting an uncoupling between resorption and formation. Isocaloric protein undernutrition decreased bone mineral mass and strength. This effect might be related to decreased plasma IGF-I and/or estrogen deficiency with a consequent imbalance in bone remodeling. [source]

Characteristics of skin aging in Korean men and women

INTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 1 2005
J. H. Chung
Introduction Korea is located between Japan and Mainland China. The people of these three countries have similar appearances and it is difficult to differentiate between them. Although the population of Asia is more than half of the total population of the Earth, the inherent characteristics of Asian skin have not been well investigated. Commercial markets for cosmetics and drugs for photoaged skin are rapidly expanding in many Asian countries. Therefore, many investigators in the field of dermatology and cosmetology have become interested in brown Asian skin. Clinical characteristics of skin aging and photoaging in Asians Skin aging can be divided into two basic processes: intrinsic aging and photoaging [1]. Intrinsic aging is characterized by smooth, dry, pale, and finely wrinkled skin, whereas photoaging, which indicates premature skin aging in chronically photodamaged skin, is characterized by severe wrinkling and irregular pigmentation. The pattern of wrinkling in Asians seems to differ from that in Caucasians. Asians have coarser, thicker and deep wrinkles, particularly in the forehead, perioral and Crow's foot areas. In contrast, Caucasians usually have relatively fine cheek and Crow's foot wrinkles. The reasons for these differences are not known and need further investigation. There are racial, ethnic and genetic differences, and differences of skin structure and function, between the brown skin of Asians and the white skin of Caucasians. As Asian skin is more pigmented, acute and chronic cutaneous responses to UV irradiation differ from those in white skin. Many people believe, based on clinical impressions, that the main process of photoaging in Asians involves pigmentary changes, rather than wrinkling. However, no study has been performed to confirm this belief. Risk factors for skin wrinkles and their relative risks in Korean skin [2] Various factors such as age, sun-exposure, and smoking are known to be important risk factors for wrinkles. However, the relative risks of each factor on wrinkles in the brown skin of Asians have not been investigated, and they could differ from those in Caucasians. An evaluation system for skin wrinkling is necessary for Asian skin [3]. Thus, we developed an eight-point photographic scale for assessing wrinkles in both Korean genders [2]. This scale can probably be applied to the populations of other Asian countries, at least to the Japanese and Chinese. The pattern of wrinkles in both genders appears to be similar. Age Age is an important risk factor for wrinkling in Asians, as in Caucasians. Korean subjects in their 60s showed a 12-fold increased risk of wrinkling, while subjects in their 70s have a 56-fold increased risk compared with young age group. UV light It is well known that the UV component in sunlight can cause and accelerate photoaging. The pigmented skin of Asian may better protect skin from acute and chronic UV damage. However, we found a strong association between sun-exposure and the development of wrinkling in Koreans. It was found that sun exposure of more than 5 h per day was associated with a 4.8-fold increased risk in wrinkling versus less than 2 h of sun-exposure in Koreans. Estrogen deficiency Korean females have more wrinkles than men, after controlling for age, sun exposure, and smoking, it was found that they have a 3.6-fold increased risk of developing wrinkles than their male counterparts [2]. It has also been reported, that the relative risk for wrinkling in women is higher than in men as for in white Caucasians [4]. The reason why women show more wrinkles remains to be determined. It is possible that a reduction in skin collagen because of estrogen deficiency in postmenopausal woman may aggravate wrinkling severity. Korean women with more than 10 years since menopause showed a 3.9-fold higher risk of wrinkling than the women 5 years of beyond menopause [5]. We demonstrated that women with a history of HRT have a significantly lower risk, more specifically, one fifth of the risk of facial wrinkling relative to those who had no history of HRT. Interestingly, we found that wrinkle severity significantly increased with an increasing number of full term pregnancies. The relative risk for severe wrinkling is increased by approximately 1.8-fold per full term pregnancy. Smoking It is known that smoking causes skin wrinkling in Caucasians, and that it plays no role in Blacks [6, 7]. Koreans with have a smoking history of more than 30 pack years showed a more than 2.8-fold increased risk of wrinkles [2]. The relative risks of wrinkles associated with a 30,50 pack-years history of smoking were 2.8- and 5.5-fold, respectively. Dyspigmentation in Asian skin To follow pigmentary changes, six photographic standards for both genders were developed for Korean skin, to produce a 6-point scale [2, 8]. Hyperpigmented spots, mostly lentigines, were prominent among women, while seborrheic keratosis tended to be more prominent in men. Seborrheic keratosis in Korean men Seborrheic keratoses (SKs) are benign cutaneous tumors. They have diverse clinical and histopathological appearances and are very common in the elderly (over 50 years old). The etiology of SKs is not well understood, although patients with a great number of lesionsshow a familial trait with an autosomal dominant pattern, and human papilloma virus has been suggested as possible cause because of verrucous appearance of the lesions. Exposure to sunlight has been suggested to be a risk factor for SKs. However, there is still some debate in terms of the role of sunlight. Recently, we have investigated the clinical characteristics of SKs and relationship between SKs and sunlight exposure in Korean males [9]. The prevalence of SKs in Koreans increases with age; it rose from 78.9% at 40 years, to 93.9% at 50 years and 98.7% in those over 60 years. Exposed areas, i.e. the face, neck and dorsum of the hands, demonstrate a significant increase in the prevalence of SKs by decade, whereas partly exposed areas, although SKs tended to increase in prevalence with age, this trend was not significant. When the estimated body surface area (BSA) is taken into account, the number of SKs on both the face and dorsum of the hands (0.51 ± 0.08 per 1% BSA) was over-represented compared with the trunk. SKs were also concentrated on the neck (0.38 ± 0.07 per 1% BSA) and in the V-area (0.47 ± 0.09 per 1% BSA). Outer forearms also showed 3-fold more SKs per unit area than neighboring arms and inner forearms, which are classified as partly exposed area (0.09 ± 0.02, 0.03 ± 0.01, respectively). The total area covered by SKs on exposed area also became significantly larger with aging than on intermittently exposed areas. These results indicate that exposure to sunlight might be related to SK growth. Our results indicated that excessive sun exposure is an independent risk factor of SKs. After controlling for age, smoking, and skin type, subjects with a sun exposure history of more than 6 hours per day showed a 2.28-fold increased risk of having severe SKs (n , 6) compared with those exposed for less that 3 h per day. These findings indicated that sun-exposure may play an important role in SK development. In summary, SKs are very common in Korean males and represent one of the major pigmentary problems. SKs concentrate on exposed skin, especially on the face and dorsum of the hands. Both age and lifetime cumulative sunlight exposure are important contributing factors and may work in a synergistic manner. Conclusion Many people tend to believe that wrinkles are not a prominent feature of Asian photoaged skin, and that dyspigmentation is a major manifestation in Asian skin. Contrary to this impression, wrinkling is also a major problem in the photoaged skin of Asians, and Korean people showing severe pigmentary changes usually tend to have severe wrinkles. In conclusion, the wrinkling patterns and pigmentary changes of photoaged skin in East Asians differ from those of Caucasians, and the relative risks of aggravating factors may be different from those of Caucasian skin. References 1.,Gilchrest, B.A. Skin aging and photoaging: an overview. J. Am. Acad. Dermatol. 21, 610,613 (1989). 2.,Chung, J.H. et al. Cutaneous photodamage in Koreans: influence of sex, sun exposure, smoking, and skin color. Arch. Dermatol. 137, 1043,1051 (2001). 3.,Griffiths, C.E. et al. A photonumeric scale for the assessment of cutaneous photodamage. Arch. Dermatol. 128, 347,351 (1992). 4.,Ernster, V.L. et al. Facial wrinkling in men and women, by smoking status. Am. J. Public Health. 85, 78,82 (1995). 5.,Youn, C.S. et al. Effect of pregnancy and menopause on facial wrinkling in women. Acta Derm. Venereol. 83, 419,424 (2003). 6.,Kadunce, D.P. et al. Cigarette smoking: risk factor for premature facial wrinkling. Ann. Intern. Med. 114, 840,844 (1991). 7.,Allen, H.B., Johnson, B.L. and Diamond, S.M. Smoker's wrinkles? JAMA. 225, 1067,1069 (1973). 8.,Chung, J.H. Photoaging in Asians. Photodermatol. Photoimmunol. Photomed. 19, 109,121 (2003). 9.,Kwon, O.S. et al. Seborrheic keratosis in the Korean males: causative role of sunlight. Photodermatol. Photoimmunol. Photomed. 19, 73,80 (2003). [source]

Severe eosinophilic cystitis in a woman with anorexia nervosa

INTERNATIONAL JOURNAL OF UROLOGY, Issue 8 2006
JOE PHILIP
Abstract, Eosinophilic cystitis is a rare inflammatory disorder. It is considered to be self limiting necessitating only supportive therapy. Surgical intervention is unusual. We report here an association between eosinophilic cystitis and anorexia nervosa in an adult woman requiring radical surgery for progressive relentless disease. Estrogen deficiency associated with a possible allergic etiology could explain this association. [source]

Prostaglandin E2 Induces Expression of Receptor Activator of Nuclear Factor,,B Ligand/Osteoprotegrin Ligand on Pre-B Cells: Implications for Accelerated Osteoclastogenesis in Estrogen Deficiency

Hormonal Changes in Menopause and Implications on Sexual Health

THE JOURNAL OF SEXUAL MEDICINE, Issue 2007
Anneliese Schwenkhagen MD
ABSTRACT Introduction., The menopause is characterized by an array of changes to the female body caused by modulations which occur in the production of estrogens and androgens. The ovaries are important sites of testosterone production in the peri- and postmenopausal women, but the contribution of testosterone pro-hormones from the adrenal glands falls precipitously to the extent where the ovaries cannot correct the deficit. This results in a net decline in circulating testosterone levels. Aims., This paper gives an overview of this interesting subject area. Researchers have cogitated on the relationship between the physical effects of the menopause and the observed declines in testosterone levels, but it is now much clearer that falling testosterone levels cannot explain all of these changes. Main Outcome Measures., The cessation of follicular functioning results in a steep decline in the production of estrogens. This modulation is responsible for the physical manifestations of the menopause,hot flushes, sleep disturbances, mood changes, bleeding problems, local urogenital problems, vaginal changes, etc. Methods., A review of the pertinent literature was conducted to investigate hormonal changes around the menopause. A précis of the salient information is presented here. Results., Although the most obvious and well-known effects of the menopause are due to the decline of estrogen levels, the effects of falling testosterone levels are subtle, but by no means less significant. Reductions in sexual motivation, sexual arousal, vaginal lubrication, etc. are all associated with plummeting androgen levels. Conclusions., Today, several options exist for the treatment of the endocrinological changes associated with the menopause. Estrogen deficiency can be corrected with hormone replacement therapy and topical preparations for the genitalia. A new transdermal system for the administration of testosterone shows a great deal of potential for the treatment of androgen deficiency. Schwenkhagen A. Hormonal changes in menopause and implications on sexual health. J Sex Med 2007;4(suppl 3):220,226. [source]

Endogenous estrogen regulation of inflammatory arthritis and cytokine expression in male mice, predominantly via estrogen receptor ,

ARTHRITIS & RHEUMATISM, Issue 4 2010
Y. H. Yang
Objective A number of experimental observations have associated elevated estrogen levels with amelioration of inflammation. The involvement of estrogen and estrogen receptor (ER) isotypes in the regulation of inflammation in males is not well understood. In this study, we used specific ER, and ER, agonists in male mice deficient in estrogen because of a deletion of aromatase (aromatase-knockout [ArKO] mice) to investigate ER isotype utilization in estrogen regulation of inflammation. Methods Lipopolysaccharide (LPS)-induced cytokine expression and antigen-induced arthritis (AIA) were investigated in male ArKO and WT littermate mice, as well as in response to selective agonists of ER, (16,-LE2) and ER, (8,-VE2). The therapeutic effect of selective ER agonists was also examined in mice with collagen-induced arthritis (CIA). Results Estrogen deficiency in ArKO mice was associated with significant increases in LPS-induced serum interleukin-6 (IL-6), tumor necrosis factor, monocyte chemotactic protein 1, and interferon-, levels, which were significantly abrogated by administration of 16,-LE2, but not 8,-VE2. In contrast, both 16,-LE2 and 8,-VE2 significantly increased LPS-induced IL-10 levels. Estrogen deficiency was also associated with significant exacerbation of AIA and antigen-specific T cell proliferation, which was reversed by administration of either 16,-LE2 or 8,-VE2. ArKO mice showed increased antigen-specific T cell proliferation in response to immunization with type II collagen (CII). Administration of 16,-LE2, but not 8,-VE2, significantly reduced the severity of CIA, which was associated with inhibition of anti-CII,specific IgG. Conclusion These data indicate that endogenous estrogen plays an essential inhibitory role in inflammation in male mice and that ER, is the dominant receptor that mediates these effects. [source]

A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009
Jaya Goswami
Abstract Post-menopausal osteoporosis is considered to be an inflammatory process, in which numerous pro-inflammatory and T-cell-derived cytokines play a bone-destructive role. IL-17A is the signature cytokine of the pro-inflammatory Th17 population and plays dichotomous roles in diseases that affect bone turnover. Although IL-17A promotes bone loss in rheumatoid arthritis, it is protective against pathogen-induced bone destruction in a periodontal disease model. We used a model of ovariectomy-induced osteoporosis (OVX) in IL-17 receptor (IL-17RA),/, mice to evaluate the role of the IL-17A in bone loss caused by estrogen deficiency. Unexpectedly, IL-17RA,/, mice were consistently and markedly more susceptible to OVX-induced bone loss than controls. There were no changes in prototypical Th1, Th2 or Th17 cytokines in serum that could account for increased bone loss. However, IL-17RA,/, mice exhibited constitutively elevated leptin, which further increased following OVX. Consistently, IL-17A and IL-17F treatment of 3T3-L1 pre-adipocytes inhibited adipogenesis, leading to reduced production of leptin. In addition to its role in regulating metabolism and satiety, leptin can regulate bone turnover. Accordingly, these data show that IL-17A negatively regulates adipogenesis and subsequent leptin expression, which correlates with increased bone destruction during OVX. [source]

Functional estrogen receptors alpha and beta are expressed in normal human salivary gland epithelium and apparently mediate immunomodulatory effects

EUROPEAN JOURNAL OF ORAL SCIENCES, Issue 5 2009
Maria Tsinti
Salivary gland epithelial cells (SGECs) have been shown to participate in immunological responses and have been implicated in the pathogenesis of Sjögren's syndrome (SS). Experimental evidence from animal models indicates that estrogen deficiency may also participate in SS pathogenesis. However, the expression and functionality of the estrogen receptors alpha (ER,) and beta (ER,) in normal human salivary epithelium is unknown. To investigate these points, formalin-fixed, paraffin-embedded specimens and cultured non-neoplastic SGEC lines derived from nine minor salivary gland (MSG) biopsies with normal histology were studied. Immunohistochemical analyses detected the epithelial expression of ER,, ER,1, and ER,2 protein isoforms both in MSG tissues and in cultured SGECs. Such epithelial expression was verified by immunoblotting of various ER proteins in cellular extracts of cultured SGECs (full-length-ER,, ER,-,3, ER,1-long, ER,1-short, and ER,2-long isoforms). Estrogens did not induce growth or apoptosis in cultured SGECs. However, similarly to other cellular systems, treatment of cultured SGECs with estrogens (17,-estradiol and the ER,- and ER,-selective agonists propylpyrazole-triol and diarylpropiolnitrile, respectively) inhibited the interferon-,-inducible expression of intercellular adhesion molecule-1. This finding corroborated the functionality of ER expressed by SGEC. Our results suggest that salivary epithelium expresses constitutively functional ER, and ER, proteins that apparently mediate immunomodulatory effects. [source]

Characteristics of skin aging in Korean men and women

Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time-specific actions of sex steroids and IGF-1: Evidence from pubertal mouse models

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2010
Filip Callewaert
Abstract Although it is well established that males acquire more bone mass than females, the underlying mechanism and timing of this sex difference remain controversial. The aim of this study was to assess the relative contribution of sex steroid versus growth hormone,insulin-like growth factor 1 (GH,IGF-1) action to pubertal bone mass acquisition longitudinally in pubertal mice. Radial bone expansion peaked during early puberty (3 to 5 weeks of age) in male and female mice, with significantly more expansion in males than in females (+40%). Concomitantly, in 5,week old male versus female mice, periosteal and endocortical bone formation was higher (+70%) and lower (,47%), respectively, along with higher serum IGF-1 levels during early puberty in male mice. In female mice, ovariectomy increased radial bone expansion during early puberty as well as the endocortical perimeter. In male mice, orchidectomy reduced radial bone expansion only during late puberty (5 to 8 weeks of age), whereas combined androgen and estrogen deficiency modestly decreased radial bone expansion during early puberty, accompanied by lower IGF-1 levels. GHRKO mice with very low IGF-1 levels, on the other hand, showed limited radial bone expansion and no skeletal dimorphism. From these data we conclude that skeletal sexual dimorphism is established during early puberty and depends primarily on GH,IGF-1 action. In males, androgens and estrogens have stimulatory effects on bone size during late and early puberty, respectively. In females, estrogens limit bone size during early puberty. These longitudinal findings in mice provide strong evidence that skeletal dimorphism is determined by independent and time-specific effects of sex steroids and IGF-1. © 2010 American Society for Bone and Mineral Research [source]

Effect of Blockade of TNF-, and Interleukin-1 Action on Bone Resorption in Early Postmenopausal Women,,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2007
Natthinee Charatcharoenwitthaya
Abstract After acute estrogen withdrawal in postmenopausal women, administration of anakinra or etanercept, specific blockers of IL-1 and TNF-,, respectively, reduced the rise in bone resorption markers to about one half of that in controls. This is consistent with an important role for these immune cytokines in mediating the effect of estrogen deficiency on bone. Introduction: Studies in rodents have implicated increased production of interleukin (IL)-1, and TNF-, as mediators of bone loss after ovariectomy, but their roles are unclear in humans whose immune system differs markedly from that of rodents. Materials and Methods: We administered transdermal estradiol, 0.1 mg/d, for 60 days to 42 early postmenopausal women. Estrogen treatment was discontinued, and subjects were randomly assigned to intervention groups receiving 3 wk of injections with 0.9% saline, anakinra 100 mg/d, or etanercept 25 mg/twice weekly. Bone turnover was assessed by measuring serum carboxyl-terminal telopeptide of type 1 collagen (CTX) and amino-terminal telopeptide of type 1 collagen (NTX), markers for bone resorption, and serum amino-terminal propeptide of type 1 collagen (P1NP), a marker for bone formation. Results were expressed as percent change in markers from baseline (last 2 days of estrogen treatment and days 20 and 21 of intervention). Results: The percent changes from baseline during intervention for serum CTX, urine NTX, and serum PINP, respectively, were 43.3 ± 8.0%, 12.0 ± 7.1%, and ,41.0 ± 2.5% for the control group; 25.9 ± 6.3%, 9.5 ± 4.0%, and ,37.8 ± 3.0% for the anakinra group; and 21.7 ± 5.0%, 0.32 ± 3.82%, and ,34.5 ± 3.9% for the etanercept group. Compared with the control group, the blunting of the increase in serum CTX fell just below the level of significance (p = 0.10) after anakinra treatment, whereas the blunting of the increase in serum CTX (p = 0.034) and in urine NTX (p = 0.048) were significant after etanercept treatment. Other changes were not significant. Conclusions: The data are consistent with a role for TNF-,, and possibly for IL-1,, in mediating increased bone resorption during estrogen deficiency in women. Although either cytokine blocker reduced serum CTX by about one half, the effect of combined blockade could not be tested because of concerns about toxicity. The data do not exclude direct or indirect contributory roles for RANKL or for other cytokines. [source]

Ovariectomy-Induced Bone Loss Varies Among Inbred Strains of Mice,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005
Mary L Bouxsein PhD
Abstract There is a subset of women who experience particularly rapid bone loss during and after the menopause. However, the factors that lead to this enhanced bone loss remain obscure. We show that patterns of bone loss after ovariectomy vary among inbred strains of mice, providing evidence that there may be genetic regulation of bone loss induced by estrogen deficiency. Introduction: Both low BMD and increased rate of bone loss are risk factors for fracture. Bone loss during and after the menopause is influenced by multiple hormonal factors. However, specific determinants of the rate of bone loss are poorly understood, although it has been suggested that genetic factors may play a role. We tested whether genetic factors may modulate bone loss subsequent to estrogen deficiency by comparing the skeletal response to ovariectomy in inbred strains of mice. Materials and Methods: Four-month-old mice from five inbred mouse strains (C3H/HeJ, BALB/cByJ, CAST/EiJ, DBA2/J, and C57BL/6J) underwent ovariectomy (OVX) or sham-OVX surgery (n = 6-9/group). After 1 month, mice were killed, and ,CT was used to compare cortical and trabecular bone response to OVX. Results: The effect of OVX on trabecular bone varied with mouse strain and skeletal site. Vertebral trabecular bone volume (BV/TV) declined after OVX in all strains (,15 to ,24%), except for C3H/HeJ. In contrast, at the proximal tibia, C3H/HeJ mice had a greater decline in trabecular BV/TV (,39%) than C57BL/6J (,18%), DBA2/J (,23%), and CAST/EiJ mice (,21%). OVX induced declines in cortical bone properties, but in contrast to trabecular bone, the effect of OVX did not vary by mouse strain. The extent of trabecular bone loss was greatest in those mice with highest trabecular BV/TV at baseline, whereas cortical bone loss was lowest among those with high cortical bone parameters at baseline. Conclusions: We found that the skeletal response to OVX varies in a site- and compartment-specific fashion among inbred mouse strains, providing support for the hypothesis that bone loss during and after the menopause is partly genetically regulated. [source]

An Uncoupling Agent Containing Strontium Prevents Bone Loss by Depressing Bone Resorption and Maintaining Bone Formation in Estrogen-Deficient Rats

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2005
Pierre J. Marie Ph.D.
Trabecular bone loss in estrogen deficiency is associated with enhanced bone resorption with a smaller increase in bone formation. We previously reported that low doses of strontium can increase trabecular bone volume in rodents by affecting bone resorption and formation. In this study we determined the effect of a new divalent strontium salt (S12911) on bone loss induced by E2 deficiency. Sprague-Dawley female rats (230 g, n = 15,25 per group) were sham operated or ovariectomized (OVX) and treated with 17,-estradiol (E2, 10 ,g/kg/day, sc) or S12911 by gavage at the dose of 77, 154, or 308 mg/kg/day or the vehicle. Treatment for 60 days with S12911 resulted in a dose-dependent increase in plasma, urine, and bone strontium concentrations without any deleterious effect on total or skeletal growth. OVX rats were osteopenic compared to sham rats as shown by decreased femoral dry bone weight and mineral content measured on bone ash and by DXA. Treatment of OVX rats with S12911 prevented bone loss as bone ash and bone mineral content were restored to the values in sham rats. Trabecular bone volume measured by histomorphometry on the tibial metaphysis was decreased by 46% in OVX rats and was corrected by E2. Treatment of OVX rats with S12911 increased the trabecular bone volume by 30,36%. Histomorphometric indices of bone resorption (osteoclast surface and number) were increased in OVX rats and were reduced by S12911 to the levels in sham rats. In contrast to this inhibitory effect on bone resorption, the osteoid surface, osteoblast surface, mineral apposition rate, and bone formation rate were as high in OVX rats treated with S12911 as in untreated OVX rats. In addition, plasma osteocalcin (OC) and alkaline phosphatase (ALP) levels remained elevated or were further increased in OVX rats treated with S12911. In contrast, treatment with E2 reduced both bone resorption and formation and plasma ALP and OC to the levels in sham rats. The data indicate that the divalent strontium salt S12911 is acting as an uncoupling agent that can prevent the femoral osteopenia and partially prevent the trabecular bone loss in E2-deficient rats by inhibiting bone resorption without reducing bone formation. [source]

Mice Lacking the Plasminogen Activator Inhibitor 1 Are Protected from Trabecular Bone Loss Induced by Estrogen Deficiency

Prostaglandin E2 Induces Expression of Receptor Activator of Nuclear Factor,,B Ligand/Osteoprotegrin Ligand on Pre-B Cells: Implications for Accelerated Osteoclastogenesis in Estrogen Deficiency

Protein Undernutrition-Induced Bone Loss Is Associated with Decreased IGF-I Levels and Estrogen Deficiency

The Roles of Osteoprotegerin and Osteoprotegerin Ligand in the Paracrine Regulation of Bone Resorption

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2000
Lorenz C. Hofbauer
Abstract Although multiple hormones and cytokines regulate various aspects of osteoclast formation, the final two effectors are osteoprotegerin ligand (OPG-L)/osteoclast differentiation factor (ODF), a recently cloned member of the tumor necrosis factor superfamily, and macrophage colony,stimulating factor. OPG-L/ODF is produced by osteoblast lineage cells and exerts its biological effects through binding to its receptor, osteoclast differentiation and activation receptor (ODAR)/receptor activator of NF-,B (RANK), on osteoclast lineage cells, in either a soluble or a membrane-bound form, the latter of which requires cell-to-cell contact. Binding results in rapid differentiation of osteoclast precursors in bone marrow to mature osteoclasts and, at higher concentrations, in increased functional activity and reduced apoptosis of mature osteoclasts. The biological activity of OPG-L/ODF is neutralized by binding to osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF), a member of the TNF-receptor superfamily that also is secreted by osteoblast lineage cells. The biological importance of this system is underscored by the induction in mice of severe osteoporosis by targeted ablation of OPG/OCIF and by the induction of osteopetrosis by targeted ablation of OPG-L/ODF or overexpression of OPG/OCIF. Thus, osteoclast formation may be determined principally by the relative ratio of OPG-L/ODF to OPG/OCIF in the bone marrow microenvironment, and alterations in this ratio may be a major cause of bone loss in many metabolic disorders, including estrogen deficiency and glucocorticoid excess. That changes in but two downstream cytokines mediate the effects of large numbers of upstream hormones and cytokines suggests a regulatory mechanism for osteoclastogenesis of great efficiency and elegance. [source]

Effects of long-term administration of N-3 polyunsaturated fatty acids (PUFA) and selective estrogen receptor modulator (SERM) derivatives in ovariectomized (OVX) mice

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2003
L. Zeitlin
Abstract We studied the beneficial effects of dietary consumption of n-3 polyunsaturated fatty acids (PUFA) and two selective estrogen receptor modulator (SERM) derivatives (SERM-I and SERM-II) and their combined effect on serum lipids, skin dermis and adipose layers, bone marrow adipogenesis, and cytokine secretion in mice. Two different ovariectomized (OVX) models were studied: treatment began immediately post-OVX in one and 3 months post-OVX in the other. Our results showed that n-3 PUFA and both SERMs decreased triglyceride levels in the serum, and that SERMs also decreased serum cholesterol levels while n-3 PUFA had no similar effect. SERMs had no effect on IL-6, IL-1 beta, or IL-10 levels, but they decreased ex vivo tumor necrosis factor (TNF-,). N-3 PUFA decreased secretion of non-induced IL-6 and TNF-, from cultured BMC and IL-1 beta levels in vivo (i.e., in bone marrow plasma), but its main effect was a significant elevation in the secretion of IL-10, a known anti-inflammatory cytokine. OVX-induced B-lymphopoiesis was not affected by LY-139481 (SERM-I) while LY-353381 (SERM-II) exhibited an estrogen-antagonistic effect in sham and OVX mice and elevated the amount of B-cells in bone marrow. Fish oil consumption prevented the elevation in B-lymphopoiesis caused by OVX, but had no curative effect on established augmented B-lymphopoiesis. This activity could be mediated via the elevation of IL-10 which was shown to suppress B-lymphopoiesis. Both SERMs and n-3 PUFA inhibited the increase in adipose tissue thickness caused by OVX in mice. Our results showed that n-3 PUFA, could prevent some of the deleterious outcomes of estrogen deficiency that were not affected by SERMs. We observed no significant beneficial effects of the combined administration of SERM-I, SERM-II, and PUFA on the studied parameters. The exact mechanism by which polyunsaturated fatty acids exert their activities is still not clear, but peroxisome proliferator-activated receptors (PPARs) might be involved in processes which are modulated by n-3 PUFA. J. Cell. Biochem. 90: 347,360, 2003. © 2003 Wiley-Liss, Inc. [source]

Coronary heart disease of females: lessons learned from nonhuman primates

AMERICAN JOURNAL OF PRIMATOLOGY, Issue 9 2009
Thomas B. Clarkson
Abstract The cynomolgus monkey model has contributed to significant advances regarding the understanding of coronary artery atherosclerosis of females. There are currently 8 million women in the United States living with heart disease, necessitating further study and understanding of this leading cause of morbidity and mortality for postmenopausal women. Specifically, studies involving the monkey model have allowed greater understanding of the effect of the stage of reproductive life, time since menopause, and the extent of subclinical atherosclerosis as determinates of estrogen-mediated effects on arteries. Utilizing the commonalities among monkeys and human beings, these studies have shown that postmenopausal atherosclerosis is associated with the premenopausal reproductive timeframe. In addition, monkey studies have shown that estrogen deficiency during the premenopausal stage is extremely relevant regarding the progression of atherosclerosis. After several postmenopausal years, however, studies have shown that estrogen has no beneficial effects on atherosclerosis progression and may, in fact, be deleterious. Studies using the monkey model are currently underway to investigate further uses and possibilities of postmenopausal hormone therapy for treating menopausal symptoms while protecting the breast and uterus and inhibiting the progression of coronary artery atherosclerosis. These studies will hopefully clarify the role of estrogen and eliminate the need for the possibly harmful progestin effects through the use of a highly selective estrogen receptor modulator. Am. J. Primatol. 71:785,793, 2009. © 2009 Wiley-Liss, Inc. [source]

ORIGINAL ARTICLE: Genistein Reverses Diminished T-Cell Signal Transduction, Induced by Post-Menopausal Estrogen Levels

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009
J. Preston Parry
Problem, This study addressed the ability of genistein to reverse the loss of T-cell signaling components, induced by estrogen deficiency associated with aging. Method of study, Using Jurkat 6.1 T cells, genistein regulation of CD3,, JAK3, and NF,B was analysed by Western immunoblotting at 4 or 40 pg/mL (post- and pre-menopausal levels, respectively) estradiol (E2). Corresponding gene expressions were quantified by real-time polymerase chain reaction (RT-PCR). For functionality, levels of IL-2 were correlated with its transcription by RT-PCR. Results, At 4 pg/mL E2, signaling proteins were decreased compared with 40 pg/mL: CD3,, 1.58-fold; JAK3, 1.75-fold; and NF,B, 1.73-fold (P < 0.001). Genistein, at 0.5 and 5.0 ,m, added to 4 pg/mL E2 induced their expression to 40 pg/mL levels. While significantly diminished IL-2 mRNA levels were observed at 4 pg/mL E2, genistein induced IL-2 mRNA to 40 pg/mL levels. Conclusion, Genistein restores CD3,, NF,B and JAK3 proteins and mRNAs at post-meonopausal estrogen levels, in vitro, with no significant effect at pre-menopausal estrogen levels. [source]

A novel T cell cytokine, secreted osteoclastogenic factor of activated T cells, induces osteoclast formation in a RANKL-independent manner

ARTHRITIS & RHEUMATISM, Issue 11 2009
Leonard Rifas
Objective Chronic T cell activation is central to the etiology of rheumatoid arthritis (RA), an inflammatory autoimmune disease that leads to severe focal bone erosions and generalized systemic osteoporosis. Previous studies have shown novel cytokine-like activities in medium containing activated T cells, characterized by potent induction of the osteoblastic production of interleukin-6 (IL-6), an inflammatory cytokine and stimulator of osteoclastogenesis, as well as induction of an activity that directly stimulates osteoclast formation in a manner independent of the key osteoclastogenic cytokine RANKL. This study was undertaken to identify the factors secreted by T cells that are responsible for these activities. Methods Human T cells were activated using anti-human CD3 and anti-human CD28 antibodies for 72 hours in AIM V serum-free medium to obtain T cell,conditioned medium, followed by concentration and fractionation of the medium by fast-protein liquid chromatography. Biologically active fractions were resolved using sodium dodecyl sulfate,polyacrylamide gel electrophoresis. Major bands were analyzed by mass spectrometry, and a major candidate protein was identified. This novel cytokine was cloned, and its expression was analyzed using recombinant DNA technologies. Results A single novel cytokine that could induce both osteoblastic IL-6 production and functional osteoclast formation in the absence of osteoblasts or RANKL and that was insensitive to the effects of the RANKL inhibitor osteoprotegerin was identified in the activated T cell,conditioned medium; this cytokine was designated secreted osteoclastogenic factor of activated T cells (SOFAT). Further analysis of SOFAT revealed that it was derived from an unusual messenger RNA splice variant coded by the threonine synthase,like 2 gene homolog, which is a conserved gene remnant coding for threonine synthase, an enzyme that functions only in microorganisms and plants. Conclusion SOFAT may act to exacerbate inflammation and/or bone turnover under inflammatory conditions such as RA or periodontitis and in conditions of estrogen deficiency. [source]