Abstract
Endometriosis requires medical management during a woman’s reproductive years. Most treatments aim to create a hypoestrogenic milieu, but for patients wishing to conceive, drugs that allow ...normal ovarian function are needed. Targeting angiogenesis, a hallmark of the disease, using dopamine agonists (DAs) is a promising strategy for endometriosis treatment. Herein, we review experimental and clinical data that investigate this concept. In experimental models of endometriosis, DAs (bromocriptine, cabergoline, quinagolide) downregulate proangiogenic and upregulate antiangiogenic pathways in inflammatory, endothelial and endometrial cells, blocking cellular proliferation and reducing lesion size. Impaired secretion of vascular endothelial growth factor (VEGF) and inactivation of its receptor type-2 are key events. VEGF inhibition also reduces nerve fiber density in lesions. In humans, quinagolide shows similar effects on lesions, and DAs reduce pain and endometrioma size. Moreover, a 20-fold downregulation of Serpin-1, the gene that encodes for plasminogen activator inhibitor 1 (PAI-1), has been observed after DAs treatment. Pentoxifylline, a PAI-1, increases pregnancy rates in women with endometriosis. Thus, the data support the use of DAs in the medical management of endometriosis to reduce lesion size and pain while maintaining ovulation. A combined approach of DAs and pentoxifylline is perhaps a smart way of targeting the disease from a completely different angle than current medical treatments.
This study implicates five genetic loci in bone mineral density. Two of these loci are new; three implicate genes known to be involved in bone remodeling, such as the receptor activator of nuclear ...factor-κB ligand gene (
RANKL
). Analyses showed that three of the loci are associated with osteoporotic fracture.
This study implicates five genetic loci in bone mineral density. Two of these loci are new; three implicate genes known to be involved in bone remodeling.
Osteoporosis confers substantive morbidity and mortality and associated costs and predisposes people to fragility fractures at the hip, spine, forearm, or other skeletal sites.
1
It is a common disease affecting both sexes in populations of various ancestries, although elderly women of European descent are at the highest risk.
2
Bone density is the single best predictor of osteoporotic fractures and is a valuable tool in evaluation of the risk of fractures.
3
,
4
There is abundant evidence for a genetic contribution to variation in bone mineral density, with heritability estimates between 0.6 and 0.8.
5
Bone mineral density is also influenced by environmental . . .
Although several lines of evidence point to an atherogenic role of central fat mass (CFM), few data are available to address the specific role played by peripheral fat mass (PFM).
This study was a ...cross-sectional analysis of 1356 women aged 60 to 85 years. Study variables were physical measures, CFM and PFM measured by DEXA, aortic calcification (AC) graded on lateral radiographs, lipid and glucose metabolites, blood pressure, and information on lifestyle factors and coronary disease. Peripheral fat mass showed independent negative correlation with both atherogenic metabolic risk factors and AC (P<0.001). The most severe insulin resistance-dyslipidemic syndrome and AC (score 5.10+/-0.76) was found in women with high central fat percentage (CF%, 21.7+/-0.2%) and low peripheral fat percentage (PF%, 18.3+/-0.2%, n=48). The least severe AC (score 2.45+/-0.31) was found in obese women with high CF% (21.6+/-0.1%) and high PF% (27.3+/-0.14%, n=112). The insulin resistance-dyslipidemic syndrome was also less severe compared with those with the same CF% but low PF%. The most favorable metabolic profile characterized women with low CF% (11.56+/-0.16%) and high PF% (26.86+/-0.33%, n=44). In women with a history of myocardial infarct (18.41+/-0.55%, n=45), CF% was significantly higher compared with women with no manifest coronary disease (16.48+/-0.12%, n=1210) without differences in PF%.
In elderly women, localization of fat mass is apparently more important for atherosclerosis than obesity per se; although CFM is associated with atherogenic tendencies, PFM seems to exhibit an independent dominant antiatherogenic effect.
Olamkicept selectively inhibits the cytokine interleukin‐6 (IL‐6) trans‐signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel ...disease (IBD). These first‐in‐human, randomized, placebo‐controlled, single‐ (SAD) and multiple‐ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment‐emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion‐related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose‐independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription‐3) was achieved in blood around or above olamkicept serum concentrations of 1–5 μg/mL. Overall, these results suggest that olamkicept is safe and well‐tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.
Upward trends of obesity urge more effective identification of those at cardiovascular risk. A simple dichotomous indicator, enlarged waist (> or =88 cm) combined with elevated triglycerides (> or ...=1.45 mmol/L) (EWET), was shown to offer advantages in identifying individuals with atherogenic "lipid overaccumulation" compared with other indicators, including the metabolic syndrome defined by the National Cholesterol Education Program (MS-NCEP). Whether EWET offers superior disease and event prediction in postmenopausal women, however, remains unknown.
A community-based sample of 557 women (48 to 76 years of age) were followed up for 8.5+/-0.3 years to assess the utility of EWET and MS-NCEP in estimating the risk of all-cause and cardiovascular mortality and the annual progression rate of aortic calcification. At baseline, 15.8% of women had EWET and 17.6% had MS-NCEP. All-cause mortality and cardiovascular mortality were increased in carriers of the dichotomous indicators (P<0.001). After adjustment for age, smoking, and LDL cholesterol, presence of EWET was associated with a 4.7-fold (95% CI, 2.2 to 9.8; P<0.001) increased risk and presence of MS-NCEP was associated with a 3.2-fold (95% CI, 1.5 to 6.5; P<0.001) increased risk for fatal cardiovascular events. Exclusion of women with prevalent diabetes did not change these trends; respective hazard ratios were 4.2 (95% CI, 1.9 to 9.3; P<0.001) and 2.5 (95% CI, 1.1 to 5.5; P<0.05). Among those who were discordant for EWET and MS-NCEP at baseline, those who had EWET alone (n=21) had a higher annual progression rate of aortic calcification compared with those who had MS-NCEP alone (n=31; P<0.05).
The combined presence of EWET may be the best indicator of cardiovascular risk in postmenopausal women. Other components of the MS-NCEP add little medical value to screening in general practices.
Hormone replacement therapy (HRT) is often prescribed for a few years to suppress menopausal symptoms. Although its long-term use of HRT for the primary prevention of osteoporosis is not currently ...recommended, the long-term skeletal benefits of the limited therapy are of great interest. To determine whether administration of HRT for 2–3 years in the early postmenopausal years provides long-term benefits, such as prevention of bone loss and osteoporotic fractures, we studied a group of 347 healthy postmenopausal women with normal bone mass who had earlier completed one of four placebo-controlled HRT trials and who were reexamined 5, 11, or 15 years after stopping HRT. Of these women, 263 received either HRT or placebo for 2–3 years with no further bone-sparing treatment until follow-up, and the remaining 84 women reported either prolonged or current use of HRT at reexamination. Bone mineral density (BMD) at the spine (L1–L4) and bone mineral content (BMC) in the forearm were measured at baseline, the end of the trials, and follow-up. At follow-up, we assessed the radiological presence of vertebral fracture and collected information on the new incidence of nonvertebral fractures. Compared with that of the placebo-treated women, the BMD and BMC of HRT-treated women continued to show significantly higher values (>5%) even many years after stopping HRT. After stopping treatment, the rate of bone loss returned to normal postmenopausal rates. The preservation of bone mass in the HRT group was accompanied by a significantly reduced risk of all osteoporotic fractures as compared with the placebo group OR = 0.48 (95% CI, 0.26–0.88). ‘Fast losers’ on placebo had more than a 4-fold higher risk of fractures than had the women on limited HRT with a normal rate of bone loss after withdrawal. In conclusion, limited HRT administered in the early postmenopausal years offers long-lasting benefits for the prevention of postmenopausal bone loss and osteoporotic fracture.
Estrogen deficiency has been implicated as a risk factor for cognitive impairment in elderly women, yet the role of hormone therapy (HT) to prevent this event remains controversial. The aim of this ...study was to investigate the impact of administration of HT for 2 to 3 years in the early postmenopausal years on the risk of cognitive impairment 5 to 15 years later.
We followed a group of 343 women who had received HT in randomized, placebo-controlled trials and were reexamined 5, 11, or 15 years after completion of therapy. Of these women, 261 received either HT or placebo for 2 to 3 years during the trials with no further hormone treatment until follow-up, and the remaining 82 women reported either prolonged or current use of HT at reexamination. Outcome of the study was cognitive function assessed by the short Blessed test that includes tests of orientation, concentration, and memory function on a scale of 0 to 28 (score > or =6 indicates cognitive impairment).
The mean age of participants at follow-up was 65 +/- 3 years. There was no difference in the mean cognitive scores between ever HT users and never users. For women who received 2 to 3 years of HT, the risk of cognitive impairment (cognitive score > or =6) was decreased by 64% (odds ratio OR: 0.36, 95% CI: 0.15-0.90; P = 0.03). A similar OR was found in long-term/current HT users. Adjustment for age, alcohol intake, current smoking, and education did not alter the results.
The results of the present study suggest that previous short-term HT administered in the early phase of the menopause may provide a long-term protection against cognitive impairment.
To assess the efficacy of 3 months of oral salmon calcitonin (sCT) on cartilage degradation as estimated by the changes in the urinary excretion of C-terminal telopeptide of collagen type II ...(CTX-II), and to investigate whether the response of oral sCT to urinary CTX-II depends on the baseline level of cartilage turnover.
This was a randomized, double blind, placebo-controlled clinical setting including 152 Danish postmenopausal women aged 55–85. The subjects received treatment with the different doses of sCT (0.15, 0.4, 1.0, or 2.5 mg) combined with Eligen® technology-based carrier molecule (200 mg), or placebo for 3 months. The efficacy parameter was the changes in the 24-h excretion of urinary CTX-I/II corrected for creatinine excretion at month 3.
sCT induced a significant dose-dependent decrease in 24-h urinary CTX-II excretion. Similar dose-dependent responses were found in 24-h urinary CTX-I. When stratifying the study population into tertiles of baseline urinary CTX-II, the present osteoarthritic symptoms and definite cases of osteoarthritis (OA) were significantly more frequent in women in the highest tertile of CTX-II (mean 391 ± 18 ng/mmol). Women who received 1.0 mg of sCT and had the highest cartilage turnover presented the greatest decrease in urinary CTX-II after 3 months of treatment.
In addition to its pronounced effect on bone resorption, this novel oral sCT formulation may also reduce cartilage degradation and thereby provide therapeutic benefit in terms of chondroprotection. Women with high cartilage turnover are more likely to benefit from oral sCT treatment.
Although the utility of bone mass measurements has been the subjects of extensive investigations, the number of studies comparing the predictive value of bone mass measurement at different skeletal ...sites in the same cohort with a large number of clinically verified endpoints is limited. Furthermore, scant information is available on how age at the time of diagnosis influence the risk of future fractures posed by low bone mineral density (BMD). We have followed 5,564 Danish postmenopausal women for a mean period of 7.3 years. Bone mineral content (BMC) at the forearm and BMD at the spine and hip were assessed at baseline. Vertebral fractures were assessed on digitalized images of lateral X-rays of the thoracic and lumbar spine, whereas non-vertebral fractures were self-reported. At follow-up, 17.6% of the women revealed an incidental vertebral fracture and 14.2% reported a new non-vertebral fracture. The absolute risk per 1,000 person-years of osteoporotic fracture increased significantly with decreasing bone mass at all three skeletal sites (P<0.001). Osteoporotic BMD (T-score < or =-2.5) had similar predictive values of fractures regardless of the skeletal site of measurement. Furthermore, the absolute risk of osteoporotic fractures increased significantly with increasing age at the same level of bone mass. Interestingly, the relative risk (RR) of vertebral fracture accompanying 1 SD decrease in spine BMD was similar across different age groups: <55 years (RR:2.1, 95% CI 1.3-3.3), 55-64 years (RR:2.3, 95%CI 1.7-3.2), 65-74 years (RR:2.0; 95%CI 1.5-2.6). Furthermore, women with any prior osteoporotic fracture had a 2.4-fold (95% CI 2.01-2.75, P<0.001) increased risk of a new vertebral fracture. Both age and prior fracture are strong predictors of future fractures. The long-term predictive value of bone mass measurement is independent of the site of measurement and the age at diagnosis.
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