A territory-wide real-world efficacy and toxicity analysis of abiraterone acetate versus docetaxel in 574 Asian patients with metastatic hormone-sensitive prostate cancer.

INTRODUCTION: Abiraterone acetate (ABI) or docetaxel (DOC), in addition to androgen-deprivation therapy (ADT), are current treatment options for metastatic hormone-sensitive prostate cancer (mHSPC). No randomized head-to-head trial has compared these 2 mHSPC treatments, and real-world data regarding their outcomes in Asian patients are lacking. PATIENTS AND METHODS: The medical records of mHSPC patients who began upfront ABI or DOC treatment in addition to ADT at seven public oncology centers in Hong Kong between 2015 and 2021 were reviewed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), prostate-specific antigen (PSA) response, and toxicities. Kaplan-Meier and multivariate Cox regression analyses were performed. RESULTS: A total of 574 patients were included, of whom 419 received DOC and 155 received ABI. The median follow-up duration was 22.4 (DOC group: 23.8; ABI group: 17.3) months. The ABI group demonstrated significantly better PFS than the DOC group (not reached vs. 15.1 months: hazard ratio = 0.37; 95% confidence interval = 0.28-0.50; P < .001). No significant OS difference was observed (P = .58). Failure to achieve a ≥ 90% decline in PSA level at 3 months and failure to achieve an undetectable PSA nadir were each associated with unfavorable PFS and OS. Patients who received DOC had a higher rate of febrile neutropenia, whereas those who received ABI had higher rates of grade ≥ 3 hypokalemia and elevated alanine transaminase. Treatment discontinuation due to toxicities was more common in the DOC (3.6%) than the ABI (0.6%) group. CONCLUSION: In Asian mHSPC patients, upfront ABI + ADT was associated with better PFS than DOC + ADT, with no significant OS difference. PSA kinetics may help stratify the prognosis for treatment intensification. Toxicity profiles were different, with a higher rate of toxicity-related treatment discontinuation in the DOC group.

A Systematic Review and Meta-analysis of the Effect of Oral Exercises on Masticatory Function.

The aim of the current systematic review was to summarize and to evaluate the available information on the effectiveness of oral exercise in improving the masticatory function of people ≥18 y. Electronic databases (Medline, Embase, CENTRAL) and gray literatures were searched (up to December 2020) for relevant randomized and nonrandomized controlled clinical trials. Two reviewers independently conducted the study selection, data extraction, and quality assessments. Meta-analysis was conducted for the comparison of bite force and masticatory performance using mean difference (MD) and standardized mean difference (SMD), respectively. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) assessment was adopted for collective grading of the overall body of evidence. Of the 1,576 records identified, 18 studies (21 articles) were included in the analysis. Results of meta-analysis indicated that oral exercise could significantly improve the mean bite force of the participants (parallel comparison: MD, 41.2; 95% CI, 11.6-70.7, P = 0.006; longitudinal comparison: MD, 126.5; 95% CI, 105.2-144.9, P < 0.001). However, the improvement in masticatory performance was not significant (parallel comparison: SMD, 0.11; 95% CI, -0.20 to 0.42, P = 0.48; longitudinal comparison: SMD, 0.4; 95% CI, -0.11 to 0.91, P = 0.13). Results of meta-regression showed that greater improvements in bite force can be achieved among younger adults and with more intensive exercise. Chewing exercise is the most effective oral exercise, followed by clenching exercise, while simple oral exercise may not have a significant effect. Based on the results of the meta-analysis and GRADE assessment, a weak recommendation for people with declined masticatory function to practice oral exercise is made.

The fractionation of phosphorus in UK chalk stream surface waters and its relevance to the regulation and management of water quality.

The regulatory management of river water quality requires measurements of phosphorus that are operationally viable and meaningful in terms of insight into its effects. This need is a particular concern in globally rare and ecologically sensitive chalk streams. P data pertaining to rivers are commonly limited to soluble reactive P; other fractions of P may be of concern but are not routinely monitored. This study seeks to establish the nature and extent of non-regulated forms of P in UK chalk streams. Whilst soluble reactive P in two southern English chalk streams was found to comprise the majority of reactive P in surface waters in the majority of samples, 15-20% of the total reactive P was within other size fractions greater than 0.22 µm. The contribution of reactive P to the total P was highly variable. We conclude that, with some adjustments, the established method of regulatory monitoring of P in UK rivers is viable and valuable. In cases where the levels of reactive P are not consistent with ecological status and/or expected outcomes of programmes of measures, we recommend that targeted analysis of non-regulated forms of P is undertaken as a means to guide and focus management interventions.

Topical Fluoride to Prevent Root Caries: Systematic Review with Network Meta-analysis.

The aim of this systematic review and network meta-analysis was to summarize the direct and indirect clinical evidence on the effectiveness of professionally applied and self-applied topical fluorides in preventing dental root caries. Controlled clinical trials with any follow-up duration were included. MEDLINE, PubMed, Embase, Scopus, and Cochrane Library were searched. Two reviewers independently carried out the selection of studies, data extraction, risk-of-bias assessments, and assessment of the certainty in the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Fixed effects model and frequentist approach were used in the network meta-analyses. Nine clinical trials involving 4,030 participants were included. Five professionally applied and 7 self-applied topical fluoride agents or combinations were included in the meta-analyses. Compared to control group, 38% silver diamine fluoride solution, 5% sodium fluoride varnish, and 1.2% acidulated phosphate fluoride reduced root caries increment after 2 y (ranging from 0.59 to 0.85 mean decayed or filled root [DF-root]). Fluoride mouth rinse and fluoride toothpaste, used alone or in combination, reduced root caries increment after 1 y (ranging from 0.29 to 1.90 mean DF-root). Among the professionally applied topical fluorides reviewed, an annually applied 38% silver diamine fluoride (SDF) solution combined with oral health education is most likely to be the most effective in preventing dental root caries. Among the reviewed self-applied topical fluoride methods, daily use of a 0.2% sodium fluoride (NaF) mouth rinse is most likely to be the most effective, followed by 1100 ppm to 1500 ppm fluoride toothpaste plus 0.05% NaF mouth rinse, and 1100 ppm to 1500 ppm fluoride toothpaste.

Factors Associated with Dental Root Caries: A Systematic Review.

OBJECTIVES: The objectives of this review were to identify the factors associated with root caries and to describe their relationship with the presence and extent of root caries. METHODS: A search was carried out on the PubMed, Medline, Embase, and Scopus databases for articles published between January 1990 and October 2018. Information was extracted on the factors associated with the presence or extent of decayed or filled root surfaces and/or decayed root surfaces. Factors were sorted into 6 categories: social-demographic background, general health, health behaviors, fluoride exposure, oral health habits, and oral health condition. RESULTS: The quality of the 127 identified relevant papers was assessed, and those of low methodological quality were excluded. Finally, 44 articles reporting on 40 cross-sectional studies were included. The total sample size comprised 78,183 participants from different countries around the world. Positive correlations were detected between root caries and age, gingival recession, and use of tobacco, while negative correlations were found for social position, use of fluoride toothpaste, and oral hygiene status. Mixed findings were reported for association with the number of teeth and dental visit behaviors. CONCLUSION: This systematic review found a number of factors in different categories to be associated with root caries. People who are older, of lower socioeconomic status, or tobacco users and those with more gingival recession and poorer oral hygiene have higher risk of root caries. KNOWLEDGE TRANSFER STATEMENT: This systematic review found a number of factors associated with root caries, including age, social position, exposure to fluoride, and oral hygiene status. This information helps dental public health workers and clinicians identify the groups at high risk of caries and the factors to act on for more effective prevention and management of root caries (e.g., use fluoride toothpaste and improve oral hygiene).

Simultaneous pancreas and kidney transplantation as the standard surgical treatment for diabetes mellitus patients with end-stage renal disease.

OBJECTIVES: To review the outcome following simultaneous pancreas and kidney transplantation in patients with type 1 diabetes mellitus and end-stage renal disease, as well as those with type 2 diabetes mellitus, and to discuss the applicability of this treatment in this locality. METHODS: A systematic literature review was performed by searching the PubMed and Elsevier databases. The search terms used were "simultaneous pancreas and kidney transplantation", "diabetes", "pancreas transplant" and "SPK". Original and major review articles related to simultaneous pancreas and kidney transplantation were reviewed. Papers published in English after 1985 were included. Clinical outcomes following transplantation were extracted for comparison between different treatment methods. Outcomes of simultaneous pancreas and kidney transplant and other transplantation methods were identified and categorised into patient survival, graft survival, diabetic complications, and quality of life. Patient survivals and graft survivals were also compared. RESULTS: Currently available clinical evidence shows good outcomes for type 1 diabetes mellitus in terms of patient survival, graft survival, diabetic complications, and quality of life. For type 2 diabetes mellitus, the efficacy and application of the procedure remain controversial but the outcomes are possibly comparable with those in type 1 diabetes mellitus. CONCLUSIONS: Simultaneous pancreas and kidney transplantation is a technically demanding procedure that is associated with significant complications, and it should be regarded as a 'last resort' treatment in patients whose diabetic complications have become life-threatening or severely burdensome despite best efforts in maintaining good diabetic control through lifestyle modifications and medications.

Attitude toward the out-patient cardiac rehabilitation program and facilitators for maintenance of exercise behavior.

OBJECTIVE: This study examined the attitudes of Chinese patients with coronary heart disease (CHD) toward the outpatient cardiac rehabilitation program (OCRP), as well as their exercise behavior, intention, maintenance and related factors. METHOD: A qualitative descriptive study design was used, and 22 CHD patients were recruited in Hong Kong in 2014. In-depth interviews and content analyses were conducted. The tripartite model of attitudes was adopted as research framework. RESULT: Two themes were identified: (1) informant attitude (perception, affection, and practice) toward the OCRP and (2) Exercise Behavior - intention, maintenance and its related factors. Most informants showed positive perception and affection regarding the outpatient rehabilitation program, leading to regular practice of exercise in the program and at home. Peer, group dynamic, social support and Chinese culture influences on exercise behavior may serve as major facilitators to maintain exercise behavior. CONCLUSION: Positive attitude toward the OCRP enhanced the participation rate, whereas peer and social support from the family and workplace were useful to improve the maintenance of exercise behavior. Overall, this study provides insights into strategic planning for the OCRP and continual support for CHD patients in the community.

Docetaxel chemotherapy for Chinese patients with castrate-resistant prostate cancer.

OBJECTIVE. To determine the effectiveness and toxicity of docetaxel for Chinese patients with castrate-resistant prostate cancer in a local Hong Kong hospital. DESIGN. Case series. SETTING. A tertiary cancer centre in Hong Kong. PATIENTS. In all, 39 castrate-resistant prostate cancer patients were treated with 3-weekly docetaxel at 75 mg/m(2) and prednisolone 10 mg daily between January 2006 and December 2011 in Queen Elizabeth Hospital. MAIN OUTCOME MEASURES. Prostate-specific antigen control rate, pain control rate, progression-free survival, overall survival, and complication rates. RESULTS. The prostate-specific antigen response rate was 36%, and 27 (69%) of the patients had improved pain control after chemotherapy. The median progression-free survival, cancer-specific survival, and overall survival was 7.8 (95% confidence interval, 4.9-10.8) months, 13.0 (95% confidence interval, 9.6-16.3) months, and 12.2 (95% confidence interval, 9.3-15.1) months, respectively. The grade 3 anaemia and thrombocytopenia rates were 5%, and the neutropenic fever rate was 8%. CONCLUSIONS. Chemotherapy with docetaxel at a dose of 75 mg/m(2) given once every 3 weeks together with daily prednisolone is well tolerated in Chinese and can offer good symptom palliation in suitable patients with castrate-resistant prostate cancer.

Sacrococcygeal teratoma in adults: case report and literature review.

Sacrococcygeal teratoma is one of the most common tumours in infants but rare in adults. We present a case of sacrococcygeal teratoma in a female adult. The clinical presentation, radiological and histological findings, management, and outcome are described.

Estrogenic phenol and catechol metabolites of PCBs modulate catechol-O-methyltransferase expression via the estrogen receptor: potential contribution to cancer risk.

Commercial PCB mixtures have been shown to induce liver tumors in female rats and this effect has been attributed to the effects of PCBs on estrogen metabolism. Catechol metabolites of PCBs are potent inhibitors of COMT activity and are likely to contribute significantly to reduced clearance of genotoxic catechol metabolites of estrogen. The effect of PCB metabolites on COMT expression in cultured cells was investigated to explore potential mechanisms by which PCB exposure alters catechol estrogen clearance. We hypothesize that estrogenic PCB metabolites may contribute to reduction of COMT expression via interaction with the estrogen receptor. To test this hypothesis, human MCF-7 cells were exposed to PCB analogues and the expression of COMT determined. Western blot analysis demonstrated that COMT protein levels were statistically significantly reduced by both the phenolic and the catechol compounds, an effect which was abolished by the anti-estrogen, ICI182780. The above suggests that COMT levels may be reduced by estrogenic PCB metabolites, via interactions between PCB metabolites and the ER. It supports the hypothesis that both phenolic and catechol metabolites of PCBs may contribute to PCB-mediated carcinogenesis through reduction of COMT levels and activities and subsequent reduction in clearance of endogenous and xenobiotic catechols.

Sjögren's syndrome sufferers have increased oral yeast levels despite regular dental care.

AIM: To investigate the prevalence and quantity of oral yeasts and their association with oral candidiasis in Sjögren's syndrome (SS) patients receiving regular dental care. MATERIALS AND METHODS: Yeasts in oral rinse and full-mouth supra-gingival plaque samples from 25 primary SS, 27 secondary SS and 29 control subjects were selectively cultured. All yeasts except single-species isolates were genotyped using pulsed field gel electrophoresis (PFGE). RESULTS: Ten (19%) SS sufferers had symptomless candidiasis. SS subjects had a higher prevalence (73%vs 7%) and quantity of yeasts than controls in both oral rinse and plaque samples (P < 0.05). The prevalence of yeasts in plaque was associated with candidiasis regardless of denture wearing (P < or = 0.04). Candida albicans was the predominant yeast isolated. PFGE showed 20 (66% of total) C. albicans isolate pairs, i.e. C. albicans species isolated from plaque and oral rinse samples of the same individual, were of closely related genetic clonal types (P < 0.01). CONCLUSIONS: Despite effective oral hygiene, more SS subjects than controls had detectable levels of oral yeasts and their presence in supra-gingival plaque was associated with candidiasis. Candida albicans colonized supra-gingival biofilm even in well-maintained SS individuals, posing a challenge to the control of oral candidiasis.

The efficacy of cevimeline hydrochloride in the treatment of xerostomia in Sjögren's syndrome in southern Chinese patients: a randomised double-blind, placebo-controlled crossover study.

Cevimeline hydrochloride, a specific agonist of the M3 muscarinic receptor, is beneficial in the treatment of symptoms of xerostomia and xerophthalmia associated with Sjögren's syndrome (SS). Cevimeline has not been evaluated in southern Chinese patients. Furthermore, the effects of cevimeline on health-related quality of life and oral health status are not known. In this randomised, double-blind, placebo-controlled crossover study, patients received cevimeline 30 mg or matched placebo three times per day over 10 weeks followed by a 4-week washout period before treatment crossover. Participants self-completed the following questionnaires: Xerostomia Inventory (XI), the General Oral Health Assessment Index (GOHAI), the Ocular Surface Disease Index (OSDI) and the Medical Outcomes Short Form (SF-36). Clinical assessments included sialometry, examination of the oral cavity for the degree of xerostomia and dental complications of xerostomia. Fifty patients (22 primary SS and 28 secondary SS) were enrolled in the trial. Forty-four patients completed the study. There was a significant improvement in the XI and GOHAI scores as well as the objective rating of xerostomic signs of the oral cavity after treatment with cevimeline. However, there was no improvement in salivary flow rates and dry eye symptoms. SS patients had lower SF-36 scores, but these did not improve after treatment with cevimeline.

Supra-gingival microbiota in Sjögren's syndrome.

The aim of this study was to investigate the microbiota of noncaries associated supra-gingival plaque (SGP) microbiology in Sjögren's syndrome (SS). Stimulated whole saliva (SWS) and full-mouth SGP on intact tooth surfaces were collected from 26 primary (p) SS, 27 secondary (s) SS, and 29 control subjects for selective culture of lactobacilli, mutans streptococci, and aerobic and facultatively anaerobic gram-negative rods (AGNR). Predominant cultivable anaerobes from SGP of 11 randomly selected subjects from each group were investigated. Clinical and sialometric data were also collected. SS sufferers had significantly lower SWS flow rate and higher mean DMFT (decayed, missing, filled teeth), while pSS subjects also had lower SWS pH and fewer standing teeth. Lactobacillus acidophilus levels in SWS (P = 0.012) and SGP (P < 0.0001) were significantly elevated in pSS sufferers compared with sSS individuals and controls. AGNR isolation was uncommon. SS sufferers had significantly lower proportion of gram-negative species (P = 0.047). Non-oral species were isolated in greater proportions from pSS SGP (P = 0.007). Subjects with pSS harbored increased levels of L. acidophilus and non-oral species, while SS sufferers generally had lower proportions of gram-negative species. The microbial composition of noncaries associated SGP indicates a potential source of increased caries risk in SS.

Influence of demographic factors and sport type on growth hormone-responsive markers in elite athletes.

CONTEXT: GH-responsive markers of the IGF system and of collagen turnover hold promise as the basis of a GH doping test. OBJECTIVE: The purpose of this study was to determine the influence of age, gender, body mass index (BMI), ethnicity, and sporting type on GH-responsive serum markers in a large cohort of elite athletes from different ethnic backgrounds. DESIGN: The study was designed as a cross-sectional study. PARTICIPANTS: A total of 1103 elite athletes (699 males, 404 females), aged 22.2 +/- 5.2 yr, from 12 countries and 10 major sporting categories participated in this study. MAIN OUTCOME MEASURES: Serum IGF-I, IGF binding protein-3 (IGFBP-3), acid labile subunit (ALS), and collagen markers [N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), N-terminal propeptide of type III procollagen (PIIINP)] were measured. RESULTS: There was a significant negative correlation (r = -0.14 to -0.58, P < 0.0005) between age and each of the GH-responsive markers. Serum IGF-I, IGFBP-3, and ALS were all lower (P < 0.05), whereas the collagen markers PINP, ICTP, and PIIINP were higher (P < 0.05) in men than in women. Multiple regression analysis indicated that age, gender, BMI, and ethnicity accounted for 23-54% of total between-subject variability of the markers. Age and gender cumulatively accounted for 91% of the attributable variation of IGF-I and more than 80% for PINP, ICTP, and PIIINP. Gender exerted the greatest effect on ALS (48%), and BMI accounted for less than 12% attributable variation for all markers. The influence of ethnicity was greatest for IGFBP-3 and ALS; however, for the other markers, it accounted for less than 6% attributable variation. Analysis of 995 athletes indicated that sporting type contributed 5-19% of attributable variation. CONCLUSIONS: Age and gender were major determinants of variability of GH-responsive markers except for IGFBP-3 and ALS. Ethnicity is unlikely to confound the validity of a GH doping test based on IGF-I and these collagen markers.

A two-stage refinement approach for the enhancement of excretory production of an exoglucanase from Escherichia coli.

Hyper-expression of a secretory exoglucanase, Exg, encoded by the cex gene of Cellulomonas fimi was previously shown to saturate the SecYEG pathway and result in dramatic cell death of recombinant Escherichia coli (Z.B. Fu, K.L. Ng, T.L. Lam, W.K.R. Wong, Cell death caused by hyper-expression of a secretory exoglucanase in Esherichia coli, Protein Expr. Purif. 42 (2005) 67-77). We propose here that the cell lysate ratio (Pre/Mat RQ) of the unprocessed precursor Exg protein (Pre-Exg) and its processed mature product (Mat-Exg) reflects the capacity of E. coli to secrete Exg. A Pre/Mat RQ of 20/80, designated the "Critical Value," was an important threshold measurement. A rise in the Pre/Mat RQ triggered a mass killing effect. The use of various secretion signal peptides did not improve the viability of cells expressing high levels of Pre-Exg under strong tac promoter control. However, use of the weaker vegG promoter in conjunction with a change in start codon of the spa leader sequence from ATG to TTG in a pM1vegGcexL plasmid construct resulted in a high level (0.9 U ml(-1)) of excreted Exg in shake-flask cultures. This was 50% higher than the best result obtained from plasmid construct lacUV5par8cex, using the lacUV5 promoter and the ompA leader sequence. Variations in the excreted Exg activities were attributable to differences in the Pre/Mat RQ values of the induced cultures harboring pM1vegGcexL and lacUV5par8cex. These values were 18/82 and 10/90, respectively. Employing fed-batch cultivation in two-liter fermentors, an induced JM101(pM1vegGcexL) culture yielded 4.5 U ml(-1) of excreted Exg, which was over six fold greater that previously reported. Our results illustrate the successful application of the Pre/Mat RQ ratio as a guide to the attainment of a maximum level of secreted/excreted Exg.

Oral health-related quality of life of stroke survivors on discharge from hospital after rehabilitation.

The study aimed to investigate oral health-related quality of life (OHR-QoL) of stroke survivors on hospital discharge after rehabilitation. It was a cross-sectional study involving 43 elderly survivors of mild to moderate stroke about to be discharged from hospital after rehabilitation and a comparison group of 43 community-dwelling elderly people. The Medical Outcomes Short Form 36 (SF-36) measure, the General Oral Health Assessment Index (GOHAI) and an oral health transition scale were administered prior to a dental examination. Median SF-36 subscale scores were significantly different between groups (P < 0.05). In physical function, role-physical, role-emotional and mental health domains, stroke survivors had significantly lower scores indicating poorer health. The median GOHAI score for the stroke group was 52 and 54 for the comparison group with no significant difference between groups although more stroke survivors had difficulty speaking compared with the comparison group. About 75% of stroke survivors considered their appearance to be worse, half of them felt that speech was worse and about a third had difficulty chewing hard food compared with the pre-stroke condition (P < 0.05). Most participants were partially dentate with no significant difference in DMFT scores or prosthetic status between groups (P > 0.05). Health-related quality of life in general was significantly poorer after stroke although patients were considered physically well enough to be discharged from hospital. There was some impairment of OHR-QoL. The nature of the stroke, the hospital environment including diet, coping strategies and elderly Chinese peoples' perception of health should be taken into account when interpreting measures of health status in stroke survivors.

Impact of Sjögren's syndrome on oral health-related quality of life in southern Chinese.

The effect of oral symptoms of Sjögren's syndrome (SS) on health-related quality of life is presently uncertain. This study aimed to investigate oral health-related quality of life (OHRQOL) among southern Chinese people with SS. Twenty-six primary SS cases, 25 secondary cases and 29 matched controls took part in this cross-sectional study. Each participant completed a SF-36 questionnaire, the Oral Health Impact Profile and a dry mouth measure, assisted by a trained interviewer. Data on socio-demographic variables were also collected. The dry mouth measure revealed that people with primary and secondary SS had significant problems associated with subjective symptoms of dry mouth generally, and dry mouth when eating and speaking (P < 0.01). Sticky saliva and coughing were also problems in some primary SS cases. OHIP summary and sub-scale scores did not reveal differences in negative impacts between groups. Mean SF-36 sub-scale scores were significantly different between groups (P < 0.05). In physical function, role-physical and general health domains, primary and secondary SS sufferers had lower scores indicating poorer health. Oral symptoms of SS, notably xerostomia, had a negative effect on OHRQOL. Health-related quality of life in general was also impaired in SS sufferers. The OHIP did not appear to discriminate oral problems of concern to SS sufferers.

Metabolic effects of oestrogens: impact of the route of administration.

To investigate whether oestrogen modulates GH secretion and action in adult life, we studied the impact of oestrogen replacement on circulating GH and IGF-I levels in post-menopausal women. Since the liver is the major source of circulating IGF-I and the oral route of oestrogen delivery causes non-physiologic effects on hepatic proteins, we compared the effects of oral and transdermal route of delivery. Oral ethinyl oestradiol administration resulted in a significant fall in mean IGF-I levels and a 3-fold increase in mean 24h GH. Transdermal administration of 17beta oestradiol resulted in a slight increase in serum IGF-I but no change in mean 24h GH levels. To determine whether differences in oestrogen type rather than in the route of delivery caused the different effects on the GH/IGF-I axis, we compared the effects of three oral oestrogen formulations. Ethinyl oestradiol, conjugated equine oestrogen and oestradiol valerate each induced a fall in IGF-I and a rise of mean 24h GH levels in post-menopausal women. To determine the metabolic significance of oestrogen-induced changes on GH/ IGF-I, we compared the effects of 24 weeks each of oral and transdermal oestrogen on energy metabolism and body composition in 18 post menopausal women in an open-label randomised cross-over study. When compared to the transdermal route, oral oestrogen reduced lipid oxidation, increased fat mass and reduced lean body mass. Oestrogen causes distinct, route dependent effects on the somatotrophic axis. The dissociation of the GH/IGF-I axis by the oral route is likely to arise from impaired hepatic IGF-I production which causes increased GH secretion through reduced feedback inhibition. The route of oestrogen therapy confers divergent effects on substrate oxidation and body composition. The suppression of lipid oxidation during oral oestrogen therapy may increase fat mass while the fall in IGF-I may lead to a loss of lean body mass. The route dependent changes in body composition observed during oestrogen replacement therapy may have important implications for post-menopausal health and oestrogen use in general.

Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2.

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.