Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause 11

ABSTRACT Objective: There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. We have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore we hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer. Design: This was a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia. Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported in the medical literature and to age-specific local population rates. Results: There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years-substantially less than women receiving estrogen/progestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the "Million Women" Study (521 per 100,000 woman-years). The breast cancer rate in our testosterone users was closest to that reported for hormone therapy never-users in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population in South Australia. Conclusions: These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population

Aquaporin-1 Water Channel Expression in Human Kidney

The pattern of aquaporin-1 water channel protein (AQP1) expression in the human kidney was analyzed by immunocytochemistry using semi-thin and optimized high-resolution immunoelectron microscopy based on freeze-substituted and Lowicryl HM20 embedded tissue. In addition, in situ hybridization was used to determine AQP1 mRNA distribution. Immunoblots revealed a 28-kd band and a 35- to 45-kd band corresponding to unglycosylated and glycosylated AQP1. Glomerular capillary endothelium exhibited extensive AQP1 labeling, whereas glomerular podocytes and Bowman's capsule epithelium were unlabeled. AQP1 was localized in the proximal tubule, including the neck region directly connected to the glomerulus. However, there was a marked difference in the level of expression between cross-sections of the convoluted part and the proximal straight tubules, the latter displaying the most intense labeling. AQP1 labeling continued uninterrupted from the proximal straight tubule into descending thin limbs in outer medulla. Abrupt transitions from heavily labeled to unlabeled segments of thin limbs were observed, primarily in the inner medulla. This may represent the transition from the water-permeable thin descending limb to the water-impermeable thin ascending limb. In addition, heavy labeling of fenestrated endothelium was also observed in peritubular capillaries in cortex, outer medulla, and inner medulla. Immunolabeling controls were negative. In situ hybridization documented a marked difference in AQP1 mRNA levels within the proximal tubule, with the greatest AQP1 mRNA expression in straight proximal tubules. Glomeruli also showed marked signals, and descending thin limbs exhibited extensive expression in exact concordance with the immunocytochemical results. It was concluded that: (1) AQP1 is present in all proximal tubule segments, including segment 1 and the neck region, but there is a pronounced difference in expression levels with respect to both protein and mRNA levels; (2) AQP1 labeling is observed in the endothelium of fenestrated peritubular capillaries, as well as fenestrated glomerular capillaries; (3) AQP1 labeling continues directly from proximal tubules to descending thin limbs; and (4) abrupt transitions from labeled to unlabeled thin limb epithelium are noted

Co-expression of estrogen receptor-alpha and targets of estrogen receptor action in proliferating monkey mammary epithelial cells

INTRODUCTION: Failure to detect co-expression of estrogen receptor-alpha (ERα) and proliferation 'markers' such as Ki67 in human mammary epithelium led to the view that estrogen acts indirectly to stimulate mammary epithelial proliferation. The mitotic index was so low in prior studies, however, that transient co-expression of ERα and Ki67 during the cell cycle could have been below detection limits. METHODS: Immunohistochemistry was used on mammary tissue sections from estrogen treated rhesus monkeys to investigate co-expression of ERα and the proliferation antigen Ki67. Using the same methods, we investigated the cell localization of proteins involved in estrogen-induced proliferation, including cyclin D1, stromal cell-derived factor (SDF)-1, and MYC. RESULTS: ERα was co-expressed with the proliferation marker Ki67 as well as with SDF-1, MYC and cyclin D1 in mammary epithelial cells from estrogen-treated monkeys. CONCLUSION: ERα is expressed in proliferating mammary epithelial cells together with the estrogen-induced proteins MYC, cyclin D1 and SDF-1, consistent with a direct mitogenic action by estrogen in primate mammary epithelium

Proceedings from the Turner Resource Network symposium: The crossroads of health care research and health care delivery

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural “Turner Resource Network (TRN) Symposium” brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: 1. inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; 2. investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant 1R13HD079209-01)March of Dimes Birth Defects FoundationAmerican Heart AssociationNational Institutes of Health (U.S.) Office of Women's HealthLeaping Butterfly MinistryTurner Syndrome Society of the United State

Volume CXIV, Number 4, November 7, 1996

Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population.Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014.Results: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto's thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%.Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespa

Androgens and the breast

Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation