Abstract
Tiny RNA molecules in adipose tissue may cause insulin resistance in women with polycystic ovary syndrome, and perhaps in all women.
It is estimated that approximately 70% of women with polycystic ovary syndrome (PCOS) have intrinsic insulin resistance that cannot be attributed to body mass, such as dysfunctional glucose metabolism in adipose tissue (AT). A research team led by Ricardo Azziz (Georgia Regents University, GA, USA) recently investigated the underlying reasons behind insulin resistance in some PCOS patients.
Over the course of 4 years the researchers obtained fat biopsies from PCOS patients and carefully matched controls. Azziz explained to Women's Health that the objective was to identify abnormalities in microRNA regulation, among the “myriad of other molecular signaling factors”, which required “careful step-by-step detective work in the laboratory”. In particular, they examined the roles of microRNAs associated with regulation of the IRS/PI3K/AKT pathway in the AT of PCOS patients and controls. The investigators found that PCOS patients and controls with insulin resistance showed overexpression of miR-93 and a decreased expression of GLUT4, a key protein that regulates glucose usage in adipose tissues. While inhibition of miR-93 activity led to increased GLUT4 expression, the expression of GLUT4 is believed to be directly regulated by miR-93 through targeting of GLUT4 3′UTR. However, they also found that the PCOS AT had a microRNA profile that differed from controls in certain aspects. They found two other microRNAs, miR-133 and −233, that were overexpressed in the AT of PCOS women, but not in controls. It has previously been demonstrated that these molecules regulate GLUT4 expression, but this has only been shown in cardiomyocytes. The fact that this aspect of the microRNA profile was exclusive to PCOS patients suggests a notable model of insulin resistance in PCOS.
These results suggest a novel mechanism underlying insulin resistance, with overexpression of miR-93 and resulting low GLUT4 levels. This appears to be a characteristic signature involved in some general insulin resistance cases, with a more pronounced effect in all PCOS cases. Azziz explained that these results suggest the “presence of a unique molecular defect for which a specific drug or therapy could be designed for. The fact that this molecular defect was observed in fat tissue, independent of degree of overweightness (obesity), also indicates that fat, which can be considered the largest endocrine organ in the body, may demonstrate unique defects in PCOS and IR.” Work needs to be performed to fully understand how microRNAs are involved in glucose regulation in adipose tissue, not just in PCOS patients, but in all women.
Source: Chen YH, Heneidi S, Lee JM et al miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes doi:10.2337/db12-0963 (2013) (Epub ahead of print).
Bone of contention surrounding depot medroxyprogesterone acetate finally removed?
It has long been thought that depot medroxyprogesterone acetate (DMPA), the injectable progesterone-only contraceptive, reduces serum estrogen levels and is associated with a reversible loss of bone mineral density. However, the extent to which this osteoporotic effect influences fracture risk has been debated. A retrospective cohort study, recently published in Obstetrics & Gynecology, sought to provide an answer to this controversial issue by assessing whether DMPA use increases fracture risk.
The study utilized the UK General Practice Research Database, with data going back 18 years, to carry out a retrospective cohort study comparing fracture incidence in DMPA users with users of non-DMPA hormonal contraceptives. The group identified 11,822 fractures in 312,395 women during 1,722,356 person-years of follow-up. As well as comparing fracture incidence during the use of the contraceptive, the researchers hoped to gain further insight by investigating fracture incidence prior to the use of the contraceptive.
The study showed that once contraceptive use had commenced, the crude fracture incidence was 9.1 per 1000 person-years for DMPA users and 7.3 for nonusers. Taken alone, these results initially seem to uphold the general consensus in the field that women using DMPA as their form of contraceptive have a modest increase in fracture risk compared with women who use non-DMPA contraceptives. Interestingly, however, the study showed that before contraceptive use had started, DMPA users had a higher fracture risk than nonusers (incidence rate ratio: 1.28; 95% CI: 1.07–1.73). Moreover, fracture risk in DMPA users did not increase after starting DMPA (incidence rate ratio after/before: 1.08; 95% CI: 0.92–1.26). Therefore, it would appear that the increased risk of fracture in DMPA users exists prior to the use of the contraceptive.
The results of this study suggest that DMPA does not increase the risk of fracture, which may help alleviate the concerns sometimes associated with DMPA, since it was issued a black box warning by the US FDA. The results may also influence the way fracture risks are investigated in women using various contraceptives.
Source: Lanza LL, McQuay LJ, Rothman KJ et al. Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture. Obstet. Gynecol. 121(3), 593–600 (2013).
Smoking may have a worse effect on urothelial cancer prognosis in women than in men
Researchers led by Shahrokh Shariat, (Weill Medical College of Cornell University and New York-Presbyterian Hospital, NY, USA) recently investigated the gender-specific effects of smoking habits and smoking exposure on the outcomes of upper tract urothelial carcinoma (UTUC), following radical nephroureterectomy (RNU). Their research, published in BJU International, suggests that smoking has a gender-specific effect on treatment outcome for UTUC, with a worse prognosis for women than men.
The researchers analyzed a total of 864 patients with UTUC, comprising 553 men and 311 women, who had all undergone RNU without neoadjuvant chemotherapy to treat UTUC. Cumulative smoking exposure was categorized as “light short-term (≤19 cigarettes per day [CPD] and ≤19.9 years), moderate (all combinations except light short-term and heavy long-term) and heavy long-term (≥20 CPD and ≥20 years).” The smoking history of the patients was assessed and in total, 28.2% of the cohort were never smokers, 34.4% were former smokers and 37.4% were current smokers. Measurements such as the quantity of CPD, smoking duration in years and years since smoking cessation were used to assess smoking history.
The results demonstrated no differences in smoking status, quantity and duration between the genders. In “female ever smokers, 30 (9.6%), 121 (38.9%) and 67 (21.5%) were light short-term, moderate and heavy long-term smokers, respectively. Compared with men, female current smokers were more likely to experience disease recurrence in univariable analysis (p = 0.013).” Furthermore, in heavy long-term smokers, cancer recurrence was seven-times more likely in women than men (hazard ratio [HR]: 1.7; p = 0.03) and cancer-specific mortality (HR: 2.0; p = 0.009) was twice as high in females compared with males. Thus, females who are current and heavy long-term smokers appear to experience worse outcomes than their male counterparts.
From these results, the researchers concluded that the impact of smoking on the outcome of UTUC after RNU is gender-specific. In the published work the group stated that “further research is needed to elucidate the biological mechanisms underlying the gender-specific differential effect of smoking on UTUC outcomes.” However, the work does suggest that a greater emphasis could be placed on smoking prevention to protect against urothelial cancer, especially in women.
Source: Rink M, Xylinas E, Trinh QD et al. Gender-specific effect of smoking on upper tract urothelial carcinoma outcomes. BJU Int. doi:10.1111/bju.12014 (2013) (Epub ahead of print).
Newly discovered protein could help women fight off sexually transmitted infections
IFNs are effector cytokines whose expression is induced when the innate immune system detects a pathogen. Typically, type I IFNs are induced by a number of known pattern-recognition receptor pathways, such as by Toll-like receptor ligands (TLR) or by IFN response factors (IRFs). Recently, Paul Hertzog (Monash University, Victoria, Australia) and his fellow researchers published research concerning a newly discovered protein that could potentially help women fight off sexually transmitted infections (STIs).
The investigators classified the newly discovered protein, which they named IFN-ε, as a type I IFN, as it signaled via Ifnar1 and Ifnar2 receptors to induce IFN-regulated genes. However, unlike other IFNs, IFN-ε is not induced by known pattern-recognition receptor pathways. Instead, its expression was found to be constitutive in epithelial cells of the female reproductive tract (FRT). In addition, the expression levels of IFN-ε were found to be under hormonal regulation. The researchers used knockout mice deficient in IFN-ε to investigate the effect of IFN-ε on the susceptibility to infection. The knockout mice showed a greater susceptibility to infection of the FRT by common STIs, herpes simplex virus 2 and Chlamydia muridarum.
The researchers concluded that IFN-ε may have potent antipathogenic properties. The biological mechanisms underlying these properties remain to be elucidated. Furthermore, IFN-ε could be an immunoregulatory cytokine that exerts a stimulating effect on immune cells in the FRT. Further research is needed to elucidate the protective capacity of IFN-ε and to determine whether or not we can harness the protective potential of this protein to tackle STIs.
Source: Fung KY, Mangan NE, Cumming H et al. Interferon-ε protects the female reproductive tract from viral and bacterial infection. Science 339(6123), 1088–1092 (2013).
Anti-inflammatory effect of aspirin may lower skin cancer risk in postmenopausal women
The association between NSAIDs such as aspirin and decreased risk of cancer has been observed in gastric, colorectal and breast cancer. However, as a result of inconsistencies, the impact of NSAIDs on the risk of melanoma, a severe type of skin cancer, has been difficult to validate. Jean Tang (Stanford University School of Medicine and Cancer Institute, CA, USA) and colleagues have recently evaluated the association between NSAID use and cutaneous melanoma risk in the Women's Health Initiative Observational Study in an attempt to iron out these inconsistencies.
The group assessed 59,806 postmenopausal Caucasian women aged 50–79 years with a median follow-up period of 12 years to assess melanoma development in relation to aspirin and NSAID use. “Cox proportional hazard models were constructed after adjusting for participant skin type, sun exposure history and medical indications for NSAID use among other confounders.” During the follow-up, they recorded a total of 548 incident melanomas, which were confirmed by medical review.
Women who used aspirin had a 21% lower risk of melanoma (hazard ratio: 0.79; 95% CI: 0.63–0.98) relative to nonusers. Researchers found that taking aspirin for longer was associated with a lower risk; for example, each incremental increase in duration of aspirin use (<1, 1–4 and ≥5 years) was associated with an 11% lower risk of melanoma for each categorical increase (ptrend = 0.01). Furthermore, women with ≥5 years of use had a 30% lower melanoma risk (hazard ratio: 0.70; 95% CI: 0.55–0.94). By contrast, use of nonaspirin NSAIDs and paracetamol showed no association with melanoma risk.
In this study, postmenopausal women who used aspirin appeared to have a significantly lower risk of melanoma. In addition, the longer duration of aspirin use seemed to correlate with lower risk. These findings suggest that the chemopreventive properties of aspirin may possibly extend to include melanoma, alongside a number of other cancers. However, further investigation is needed to see whether the chemopreventive benefits outweigh any potential negative side effects associated with long-term aspirin use.
Source: Gamba CA, Swetter SM, Stefanick ML et al. Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the Women's Health Initiative. Cancer doi:10.1002/cncr.27817 (2013) (Epub ahead of print).