The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor α signaling.

Plasmacytoid dendritic cells (pDCs) produce large amounts of type I interferons (IFN-α/ß) in response to viral or endogenous nucleic acids through activation of their endosomal Toll-like receptors (TLR-7 and TLR-9). Enhanced TLR-7-mediated IFN-α production by pDCs in women, compared with men, has been reported, but whether sex hormones, such as estrogens, are involved in this sex-based difference is unknown. Here we show, in humanized mice, that the TLR-7-mediated response of human pDCs is increased in female host mice relative to male. In a clinical trial, we establish that treatment of postmenopausal women with 17ß-estradiol markedly enhances TLR-7- and TLR-9-dependent production of IFN-α by pDCs stimulated by synthetic ligands or by nucleic acid-containing immune complexes. In mice, we found exogenous and endogenous estrogens to promote the TLR-mediated cytokine secretion by pDCs through hematopoietic expression of estrogen receptor (ER) α. Genetic ablation of ERα gene in the DC lineage abrogated the enhancing effect of 17ß-estradiol on their TLR-mediated production of IFN-α, showing that estrogens directly target pDCs in vivo. Our results uncover a previously unappreciated role for estrogens in regulating the innate functions of pDCs, which may account for sex-based differences in autoimmune and infectious diseases.

Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.

OBJECTIVE: Evaluation of the use of testosterone therapy for hypoactive sexual desire disorder (HSDD) after oophorectomy has mostly involved women treated with oral estrogen preparations. We investigated the efficacy and safety of a testosterone patch in surgically menopausal women receiving concurrent transdermal estrogen. DESIGN: Women with HSDD after oophorectomy, for whom this was a concern, who were using transdermal estrogen, were recruited to a 24-week, randomized, double-blind, placebo-controlled trial in Europe and Australia. Patients were randomly allocated to placebo (n = 40) or testosterone 300 microg/day (n = 37) treatment. Primary endpoints were changes in sexual desire measured by the sexual desire domain of the Profile of Female Sexual Function and the frequency of satisfying sexual activity at 24 weeks. RESULTS: Sixty-one women (79%) completed the trial. All subjects who received at least one application of study medication were included in analysis. The testosterone-treated group experienced a significantly greater change from baseline in the domain sexual desire score compared with placebo (change from baseline, 16.43 versus 5.98; P = 0.02). The domain scores for arousal, orgasm, decreased sexual concerns, responsiveness, and self-image as well as decreased distress were also significantly greater with testosterone therapy than placebo. The frequency of satisfactory sexual events increased but was not statistically different between treatment groups (P = 0.06) Adverse events occurred with similar frequency in both groups, and no serious risks of therapy were observed CONCLUSIONS: In this study, transdermal testosterone therapy via a skin patch improved sexual desire and other sexual function domains. It was well tolerated in these oophorectomized women with HSDD receiving concomitant transdermal estrogen.

Aromatase and regulation of bone remodeling.

Estrogens play a key role in regulating bone mineralization. Bone tissue expresses the enzymes that metabolize estrogens, as well as the alpha and beta receptors that mediate responses to estrogens. After the menopause, estrogen secretion by the ovaries is promptly replaced by production within tissues, which occurs chiefly via aromatization of adrenal steroids. Therefore, aromatase activity is a major determinant of estrogen activity in postmenopausal women. Studies are beginning to shed light on the mechanisms by which aromatase activity influences bone remodeling.

[Hormone replacement therapy in the management of postmenopausal osteoporosis and prevention of fracture risk]. / Place du traitement hormonal substitutif dans la prise en charge de l'ostéoporose postménopausique et la prévention du risque fracturaire.

The consequences to the bone of estrogen deficiency are early and irreversible. Effective prevention of postmenopausal osteoporosis at the individual level requires early screening of women at risk of fractures and their early treatment. Hormone treatment prevents bone loss and has been proven effective in preventing fractures, even in situations of low risk. The benefit/risk ratio of hormone treatment can be optimized by the choice of the 'right moment' and the 'right treatment'. HRT, administered early and for a limited period, must be integrated into a strategy of long-term osteoporosis prevention that includes using the (drug and nondrug) means most appropriate to the patient's age and clinical condition and choosing the 'right moment' and 'right treatment.'

[Management of postmenopausal osteoporosis]. / Traitement de l'ostéoporose post-ménopausique.

Current management of postmenopausal osteoporosis has benefited from several advances both in the screening or those women with the highest risk of fracture and the development of efficient drugs to reduce the occurrence of fracture. At the individual level, assessment of the risk of fracture must associate the level of bone mineral density which represents the major determinant of fracture and several clinical risk factors. Measurements of biochemical markers of bone turnover are sometimes useful to improving this risk evaluation. However, the 5- to 10-year absolute risk or fracture still needs to be determined as well as the threshold above which a therapeutical intervention should be warranted. Besides hormone replacement therapy, which indications are now more limited than before, the different therapeutical options include several anti-osteoclastic drugs and more recently new anabolic compounds. It should be now possible to anticipate a long term strategy for the prevention of osteoporosis based on an early screening of the women at higher risk of fracture as well as the optimal choice of treatment taking into account the age and underlying clinical conditions of each woman.

Association of cardiovascular risk factors with intima-media thickness of the carotid arteries in early postmenopausal women.

OBJECTIVE: The aim of this study was to examine the association between carotid intima-media thickness (IMT) and coronary heart diseases (CHD) risk factors in a large population of peri- and postmenopausal women. DESIGN: Participants in this study were 906 healthy peri- and postmenopausal women from southwestern France, 45 to 65 years old with no history of cardiovascular disease and no utilization of estrogen/hormone therapy. Women were classified either as perimenopausal (n = 240) or post-menopausal (n = 666) according both to the regularity of menses and to serum follicle-stimulating hormone and estradiol values. All women answered a questionnaire, which included 72 questions, related to the identification of familial and personal cardiovascular risk factors. Biological measurements were performed to evaluate their lipid-lipoprotein profiles and fasting glucose levels, ultrasonography was used to measure IMT and total body scanners by DXA were performed to determine the percentage of body fat. RESULTS: Multiple regression analyses were used to examine the ability of each variable to explain IMT values. Mean IMT of the right carotid artery was 0.520 (+/- 0.07) mm. Of the 906 women, 9% were currently taking lipid-lowering drugs, 12.8% and less than 2% were being treated for hypertension and diabetes, respectively. Additionally, 124 women were found to have current hypertension, 10% had a familial history of CHD, and 18% were regular smokers. In multiple regression analyses, only increasing age (P < 0.001) and systolic and diastolic blood pressure (P < 0.001) were independently and significantly associated with IMT. CONCLUSIONS: These results show that only a few risk factors were associated with IMT in this population of healthy peri- and postmenopausal women. These results might be related to the fact that this study was conducted in an area of France well known for having the lowest rates of CHD in women, which is further supported by the thinner IMT found in this population as compared with a higher-risk population. Therefore, these results might not be relevant for CHD in older or high-risk women.

Prevention of postmenopausal bone loss by pulsed estrogen therapy: comparison with transdermal route.

OBJECTIVE: To compare the efficacy of pulsed estrogen therapy following intranasal 17beta-estradiol (E2) (S21400) with patch E2 in preventing postmenopausal bone loss and on bone turnover. METHODS: In this multinational open study, 361 postmenopausal women aged 51.5 (S.D. 4.6) years were treated with S21400 300 microg per day or patch E2 (delivering 50 microg per day), two patches per week, for 56 weeks. Bone mineral density (BMD) was assessed at the spine and hip using dual X-ray absorptiometry at baseline and week 56 (W56). Bone turnover markers (osteocalcin, bone alkaline phosphatase, urinary type I collagen C-telopeptides) were measured at baseline and weeks 12, 28 and 56. RESULTS: Spine and hip bone mineral density significantly increased in both groups (P < 0.001 versus baseline). Mean (S.D.) percent increases were 2.1 (3.0) at the spine (both groups), and 1.2 (2.4) and 1.1 (2.2) at the hip in the S21400 and patch E2 groups, respectively. Bone mineral density also significantly increased (P < 0.001 versus baseline) in osteopenic patients following S21400 and patch E2: 3.1 (3.5) and 2.4 (3.5) at the spine, and 2.0 (2.6) and 1.2 (2.7) at the hip, respectively. Bone metabolism was normalized at week 56 with a significant decrease (P < 0.001) from baseline in all markers: 56% and 53% for type I collagen C-telopeptides, and 24% and 25% for osteocalcin in the S21400 and patch E2 groups, respectively. CONCLUSION: Pulsed estrogen therapy was as effective in normalizing bone turnover and preventing postmenopausal bone loss as a reservoir patch.

[Current therapeutic means]. / Les moyens thérapeutiques actuels.

UNLABELLED: VARIOUS THERAPEUTIC POSSIBILITIES: Treatment of osteoporosis has greatly progressed over the past few years and, in parallel with hormone replacement therapy (HRT), new drugs (2nd and 3rd generation bisphosphonates and raloxifen) are now available, not only for primary prevention but also for secondary prevention of fractures. WHAT INDICATIONS?: The anti-fracture efficacy that has been demonstrated in large clinical trials, conducted according to the requirements of modern methodology, only appear patent in women at "high risk" for osteoporosis, i.e., those presenting a t-score < -2.5 and a prevalent fracture (particularly vertebral crushing), situation which is relatively rare at the onset of the menopause. IN PRACTICE: The initiation of such treatment in a women approaching the menopause should only be considered after prior measurement of her bone density, using a validated technique, measurement that is not always officially recognized by our Health Authorities. This problem, together with the varying conditions of prescription and reimbursement, explain some of the problems encountered in the use of these new therapeutics, notably in women at high risk of osteoporosis, who have not yet presented a fracture due to their bone fragility.

[Screening techniques]. / Les moyens de dépistage.

WOMEN "AT RISK": Assessment of the risk of osteoporosis in a woman approaching the menopause relies essentially on the evaluation of her bone mass and the study of a certain number of clinical criteria. The principle osteoporosis risk markers are age, past personal and family history of fractures due to bone fragility, low body weight, past history of early menopause and all the affections corresponding classically to "secondary" osteoporosis. OSTEODENSITOMETRY: Densitometric measurement is the corner stone of this assessment, since any decrease of 1 in the standard deviation of bone density corresponds to a two-fold greater risk of fracture. This relationship has led to a new densitometric definition of osteoporosis, based on a decrease of more than 2.5 standard deviations compared with the median value of a young adult (t-score < -2.5). THE INTEREST OF BIOCHEMICAL MARKERS: The interest of bone remodeling biochemical markers has not been clearly defined. Combined with densitometric measurements, they may permit the assessment of the level of bone remodeling and hence estimate bone loss, which is one of the determinant factors of fracture risk.

Bone mineral density and prediction of non-osteoporotic disease.

It is widely recognized that bone mineral density (BMD) is one of the best predictors of osteoporotic fractures. Sex hormone status clearly affects bone either directly or indirectly and a longer estrogen exposure appears to be a major determinant of postmenopausal BMD. Accordingly, several studies have led to the hypothesis that BMD might represent a marker of the accumulated lifetime exposure of estrogen and therefore be used as a predictor factor of the risk of other postmenopausal conditions such as breast cancer or cardiovascular diseases (CVD). With regard to the risk of breast cancer, there is evidence that different surrogate markers of lifetime exposure to estrogen are associated with an increased risk for breast cancer. Most of these markers are the opposite of those for the risk of fracture. Furthermore, several studies have also reported that women with higher BMD have an increased risk of breast cancer compared to women with lower BMD. On the other hand, postmenopausal women with osteoporosis are at increased risk for acute cardiovascular events and mortality independently of age and cardiovascular risk factors. BMD has been shown to inversely correlate with surrogate markers of CVD including aortic calcifications and atherosclerosis. The underlying mechanisms of such a relationship are not fully understood. Several plausible molecular links are serum lipids, pro-inflammatory cytokines or the RANK/RANK ligand/osteoprotegerin system. Interestingly, all of these factors are modulated by estrogens. It could thus be hypothesized that the intensity of postmenopausal estrogen deficiency could be also the common pathogenic factor between atherosclerosis and osteoporosis.

Fracture risk in early postmenopausal women assessed using FRAX.

OBJECTIVES: To evaluate FRAX 10-year fracture probabilities depending on the recommended management strategy in early postmenopausal women who were untreated at baseline. METHODS: We conducted a descriptive study in 494 untreated women aged 45-60 years seen for the first time at a menopause clinic. Risk factors, physical findings, and bone mineral density (BMD) values determined by dual-energy X-ray absorptiometry were collected. At the end of the clinic visit, 128 (26%) women were prescribed medications. Then, the 10-year fracture probability was estimated using the FRAX tool. RESULTS: The mean FRAX probability was 3.9%+/-2% for major osteoporotic fractures and 0.8%+/-0.9% for hip fractures. Women who were prescribed medications had significantly (P<0.001) higher probabilities than the other women. The proportion of women prescribed medications increased significantly (P<0.0001) with the FRAX probability, from 7.8% in the lowest quintile (Q1) to 50.5% in Q5. Hormone replacement therapy or raloxifene contributed 92% of the prescriptions in patients with FRAX probabilities in the first four quintiles and bisphosphonates 70% of prescriptions in patients with probabilities in Q5. CONCLUSIONS: Early postmenopausal women had low to moderate fracture risks (FRAX, 3-4%). The indications and type of drugs prescribed correlated with FRAX probabilities. Treatment thresholds should be defined to optimize the management of osteoporosis. In early postmenopausal women, treatment thresholds may vary with the type of treatment.

Fracture risk prediction using BMD and clinical risk factors in early postmenopausal women: sensitivity of the WHO FRAX tool.

The aim of this prospective study was (1) to identify significant and independent clinical risk factors (CRFs) for major osteoporotic (OP) fracture among peri- and early postmenopausal women, (2) to assess, in this population, the discriminatory capacity of FRAX and bone mineral density (BMD) for the identification of women at high risk of fracture, and (3) to assess whether adding risk factors to either FRAX or BMD would improve discriminatory capacity. The study population included 2651 peri- and early postmenopausal women [mean age (+/- SD): 54 +/- 4 years] with a mean follow-up period of 13.4 years (+/-1.4 years). At baseline, a large set of CRFs was recorded, and vertebral BMD was measured (Lunar, DPX) in all women. Femoral neck BMD also was measured in 1399 women in addition to spine BMD. Women with current or past OP treatment for more than 3 months at baseline (n = 454) were excluded from the analyses. Over the follow-up period, 415 women sustained a first low-energy fracture, including 145 major OP fractures (108 wrist, 44 spine, 20 proximal humerus, and 13 hip). In Cox multivariate regression models, only 3 CRFs were significant predictors of a major OP fracture independent of BMD and age: a personal history of fracture, three or more pregnancies, and current postmenopausal hormone therapy. In the subsample of women who had a hip BMD measurement and who were not receiving OP therapy (including hormone-replacement therapy) at baseline, mean FRAX value was 3.8% (+/-2.4%). The overall discriminative value for fracture, as measured by the area under the Receiver Operating Characteristic (ROC) curve (AUC), was equal to 0.63 [95% confidence interval (CI) 0.56-0.69] and 0.66 (95% CI 0.60-0.73), respectively, for FRAX and hip BMD. Sensitivity of both tools was low (ie, around 50% for 30% of the women classified as the highest risk). Adding parity to the predictive model including FRAX or using a simple risk score based on the best predictive model in our population did not significantly improve the discriminatory capacity over BMD alone. Only a limited number of clinical risk factors were found associated with the risk of major OP fracture in peri- and early postmenopausal women. In this population, the FRAX tool, like other risk scores combining CRFs to either BMD or FRAX, had a poor sensitivity for fracture prediction and did not significantly improve the discriminatory value of hip BMD alone.

Osteoporosis in otherwise healthy perimenopausal and early postmenopausal women: physical and biochemical characteristics.

Population studies have shown that about 3-5% of perimenopausal women already have osteoporosis according to the WHO definition of osteoporosis for postmenopausal women ( t -score