Gloria Y.F. Ho

Natural history of cervicovaginal papillomavirus infection in young women.

Background Genital human papillomavirus (HPV) infection is highly prevalent in sexually active young women. However, precise risk factors for HPV infection and its incidence and duration are not well known. Methods We followed 608 college women at six-month intervals for three years. At each visit, we collected information about lifestyle and sexual behavior and obtained cervicovaginal-lavage samples for the detection of HPV DNA by polymerase chain reaction and Southern blot hybridization. Pap smears were obtained annually. Results The cumulative 36-month incidence of HPV infection was 43 percent (95 percent confidence interval, 36 to 49 percent). An increased risk of HPV infection was significantly associated with younger age, Hispanic ethnicity, black race, an increased number of vaginal-sex partners, high frequencies of vaginal sex and alcohol consumption, anal sex, and certain characteristics of partners (regular partners having an increased number of lifetime partners and not being in school). The me...

Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women.

BACKGROUND The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level. METHODS We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Womens Health Initiative Observational Study (WHI-OS), a prospective cohort of 93,676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided. Results Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, P(trend) = .02); however, the association with insulin level varied by hormone therapy (HT) use (P(interaction) = .01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, P(trend) < .001). Obesity (BMI >or=30 kg/m(2)) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI >or=30 kg/m(2) vs 18.5 to <25 kg/m(2) = 2.12, 95% CI = 1.26 to 3.58, P(trend) = .003); however, this association was attenuated by adjustment for insulin (P(trend) = .40). CONCLUSION These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship.

Natural History of Human Papillomavirus Type 16 Virus-Like Particle Antibodies in Young Women

Immunization with a vaccine of human papillomavirus (HPV) type 16 virus-like particles (VLPs) can reduce incidence of HPV-16 infection and its related cervical intraepithelial neoplasia. However, development of detectable antibodies to VLPs does not always occur after natural HPV infection. This study examined prospectively for seroconversion and duration of antibodies to HPV-16 VLPs and their associated host and viral factors. Six-hundred eight subjects were tested for HPV DNA biannually and for IgG and IgA antibodies to HPV-16 VLPs annually for 3 years. Both IgG and IgA antibodies to HPV-16 VLPs were predominantly type specific. Women with cervicovaginal HPV-16 infection were 8–10 times more likely to seroconvert than those with infection of HPV-16-related types. Among subjects who had an incident infection with HPV-16, a maximum of 56.7% became seropositive for IgG within 8.3 months and 37.0% had IgA within 14 months. Detectable seroconversion was a slow process that required sufficient antigenic exposure associated with either a high viral load (relative risk = 5.7 for IgG) or persistent infection of HPV-16 (relative risk = 3.4 for IgA). The median duration for both types of antibodies was ∼36 months. Antibodies could persist for a long period of time if the initial antibody levels were high or if there was continued antigenic exposure.

Risk Factors for Subsequent Cervicovaginal Human Papillomavirus (HPV) Infection and the Protective Role of Antibodies to HPV-16 Virus-Like Particles

A high incidence of initial infection with human papillomavirus (HPV) was previously reported in a cohort of 608 women monitored at 6-month intervals for 3 years. Risk factors for subsequent infections with different HPV types and whether antibodies against HPV-16 virus-like particles (VLPs) protected against these infections were examined. Subsequent infections with HPV are very common. Seventy percent of women acquired a different HPV type within 24 months of the initial infection. Risk factors included being nonwhite, having an increased number of male sex partners, and having had a new male sex partner. Use of oral contraceptive pills was protective. A sustained high level of IgG antibody to HPV-16 VLPs was associated with reduced risk for subsequent infection with HPV-16 and its genetically related types (i.e., HPV-31, -33, -35, -52, and -58).

A Prospective Evaluation of Insulin and Insulin-like Growth Factor-I as Risk Factors for Endometrial Cancer

Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Womens Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HRq4-q1), 2.33; 95% confidence interval (95% CI), 1.13-4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HRq4-q1, 0.53; 95% CI, 0.31-0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HRq4-q1, 4.30; 95% CI, 1.62-11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data. (Cancer Epidemiol Biomarkers Prev 2008;17(4):921–9)

Insulin, Insulin-like Growth Factor-I, Endogenous Estradiol, and Risk of Colorectal Cancer in Postmenopausal Women

Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among nondiabetic subjects enrolled in the Womens Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum specimens from all incident colorectal cancer cases (n = 438) and a random subcohort (n = 816) of Womens Health Initiative Observational Study subjects were tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [hazard ratio (HR)(q4-q1), 1.73; 95% confidence interval (CI), 1.16-2.57; P(trend) = 0.005], waist circumference (HR(q4-q1), 1.82; 95% CI, 1.22-2.70; P(trend) = 0.001), and free IGF-I (HR(q4-q1), 1.35; 95% CI, 0.92-1.98; P(trend) = 0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became nonsignificant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels, 1.53; 95% CI, 1.05-2.22), even after control for insulin, free IGF-I, and waist circumference. These data suggest the existence of at least two independent biological pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I.

HPV 16 and cigarette smoking as risk factors for high‐grade cervical intra‐epithelial neoplasia

Although genital human papillomavirus (HPV) infection is well established as the etiologic agent for cervical intra‐epithelial neoplasia (CIN), little is known about the cofactors involved in the development of high‐grade lesions or the progression of low‐grade to high‐grade lesions. In our study of HPV‐infected women with CIN (163 CIN I, 51 CIN II and 44 CIN III), women with CIN II or III were compared with those with CIN I for risk factors associated with high‐grade lesions. After controlling for age, education, ethnicity and frequency of Pap smear screening, infection with HPV 16, but not high viral load or infection with multiple types, was associated with high‐grade lesions (OR for CIN II = 11.96, OR for CIN III = 23.74). Risk of CIN III, but not CIN II, increased with number of cigarettes smoked per day (ORs = 1.49 and 3.35 for ≤10 and >10 cigarettes per day, respectively) and decreased with frequency of condom use during sex (ORs = 0.60 and 0.32 for women who used condoms occasionally/sometimes and most/all of the time, respectively). There were no associations between high‐grade lesions and plasma levels of micronutrients (retinol, β‐carotene, α‐tocopherol and reduced ascorbic acid). Our results indicate that infection with HPV 16 is associated with high‐grade lesions. Additional cofactors, such as cigarette smoking, may be required as a carcinogen to advance HPV‐infected cells toward neoplastic progression. Int. J. Cancer 78:281–285, 1998.© 1998 Wiley‐Liss, Inc.

The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes.

This review addresses the possible role of the insulin‐like growth factor (IGF)‐axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF‐I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin‐like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre‐diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross‐sectionally with altered circulating levels of IGF‐I and its binding proteins (IGFBPs). Administration of recombinant human IGF‐I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF‐I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic β‐cell mass and function. There is considerable inter‐individual heterogeneity in endogenous levels of IGF‐I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association. Copyright

Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer

Experimental and epidemiological evidence suggests that circulating glucose and insulin may play a role in breast carcinogenesis. However, few cohort studies have examined breast cancer risk in association with glucose and insulin levels, and studies to date have had only baseline measurements of exposure. We conducted a longitudinal study of postmenopausal breast cancer risk using the 6% random sample of women in the Womens Health Initiative clinical trials whose fasting blood samples, provided at baseline and at years 1, 3 and 6, were analyzed for glucose and insulin. In addition, a 1% sample of women in the observational study, who had glucose and insulin measured in fasting blood samples drawn at baseline and in year 3, were included in the analysis. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for the association of baseline and follow‐up measurements of serum glucose and insulin with breast cancer risk. All statistical tests were 2‐sided. Among 5,450 women with baseline serum glucose and insulin values, 190 incident cases of breast cancer were ascertained over a median of 8.0 years of follow‐up. The highest tertile of baseline insulin, relative to the lowest, was associated with a 2‐fold increase in risk in the total population (multivariable hazard ratio 2.22, 95% confidence interval 1.39–3.53) and with a 3‐fold increase in risk in women who were not enrolled in the intervention arm of any clinical trial (multivariable hazard ratio 3.15, 95% confidence interval 1.61–6.17). Glucose levels showed no association with risk. Analysis of the repeated measurements supported the results of the baseline analysis. These data suggest that elevated serum insulin levels may be a risk factor for postmenopausal breast cancer.

Effect of 5 y of calcium plus vitamin D supplementation on change in circulating lipids: results from the Women’s Health Initiative

BACKGROUND Dietary calcium and vitamin D intakes may be inversely associated with cardiovascular disease (CVD) risk, possibly because of their potential beneficial effects on circulating lipids. Clinical trials that have evaluated the effect of calcium supplementation on lipids are limited by a short follow-up, and data on vitamin D are scarce. OBJECTIVE The objective was to evaluate the effect of a longer-term effect (over 5 y) of calcium and vitamin D (CaD) supplementation on changes in the concentrations of several lipids: LDL, HDL, non-HDL, total cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]. DESIGN The study was conducted in 1259 postmenopausal women in the Calcium plus Vitamin D Trial (1 g elemental Ca as carbonate plus 400 IU vitamin D(3)/d compared with placebo) of the Womens Health Initiative. Analyses were conducted by intention-to-treat. Repeated measurements on lipids during follow-up were analyzed by linear mixed-effects models. RESULTS Overall, the change in lipids was relatively small [< or =5% except for Lp(a), which was 20-25%], and there was no significant difference in the mean change of any lipid variable between the active and placebo groups. CONCLUSIONS Our results indicate that CaD supplementation is not associated with lipid changes over 5 y. Existing and future CaD trials should consider evaluating this association for different doses of supplements. This study was registered at clinicaltrials.gov as NCT00000611.