Ronald K. Ross

Menopausal Estrogen Therapy and Hip Fractures

Abstract The association between menopausal estrogen therapy and hip fracture was studied in a retirement community. Ninety-one hip fracture cases during a 5-year period in female residents under a...

Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China

BACKGROUND Dietary isothiocyanates inhibit lung carcinogenesis in laboratory animals but human data are limited. Glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) conjugate isothiocyanates leading to more rapid elimination. Common deletion polymorphisms of GSTM1 and GSTT1 abolish enzyme activity. We hypothesised that chemopreventive effects of isothiocyanates might be heightened when enzymes that enhance their elimination are lacking. METHODS We examined the relation between total isothiocyanate concentrations in urine, collected before diagnosis, and the subsequent risk of lung cancer among 232 incident cases of lung cancer and 710 matched controls from a cohort of 18,244 men in Shanghai, China, followed from 1986 to 1997. Homozygous deletion of the GSTM1 and GSTT1 genes were determined by PCR. FINDINGS Individuals with detectable isothiocyanates in the urine were at decreased risk of lung cancer (smoking-adjusted relative risk for lung cancer=0.65 [95% CI 0.43-0.97]). This protective effect of isothiocyanates was seen primarily among individuals with homozygous deletion of GSTM1 (0.36 [0.20-0.63]) and particularly with deletion of both GSTM1 and GSTT1 (0.28 [0.13-0.57]). INTERPRETATION Isothiocyanates appeared to reduce lung-cancer risk in this cohort of Chinese men. Reduction in risk was strongest among persons genetically deficient in enzymes that rapidly eliminate these chemopreventive compounds.

Exercise and Other Factors in the Prevention of Hip Fracture: The Leisure World Study

As part of a prospective study begun in 1981, we evaluated 8,600 postmenopausal women and 5,049 men residing in a southern California retirement community for risk factors for hip fracture. Incidence rates were twice as high in women as in men, but in both sexes the rates nearly doubled every 5 years between 70 and 90 years. Active exercise was strongly and negatively associated with hip fracture risk in both sexes; the age-adjusted relative risk was 0.6 and 0.5 for females and males, respectively, for 1 or more hours of exercise per day compared with less than 1/2 hour of exercise. A high body mass index (upper tertile of weight divided by height squared) was associated with a strong reduction in hip fracture risk for females (RR = 0.5). Current cigarette smokers had a significantly increased risk (RR = 1.8 and RR = 2.2 for females and males, respectively) compared with never-smokers, but the risk for past smokers was not different from that of lifetime nonsmokers. Other factors related to reduced hip fracture risk in women were high parity, late age at menarche, and long menstrual cycle length. These age-adjusted relative risk estimates did not change materially in multivariate analysis when adjusted simultaneously for age, active exercise, body mass, smoking, and, for women, age at menarche and number of children. Among estrogen users, the lowest risk of hip fracture was observed for recent users (RR = 0.8), while users who had stopped estrogen use 15 or more years ago had a relative risk of 1.1, suggesting that the protective effect of estrogen dissipates after many years since cessation of estrogen therapy

Aspirin use and chronic diseases: a cohort study of the elderly.

OBJECTIVE--To evaluate the associations between the use of aspirin and the incidences of cardiovascular diseases, cancers, and other chronic diseases. DESIGN--Postal questionnaire survey to elicit details of aspirin use. SETTING--Californian retirement community. SUBJECTS--All 22,781 residents of the community (white, affluent, and well educated) were sent a questionnaire that included questions on medical history and the use of drugs such as analgesics, laxatives, and vitamin supplements. In all 61% responded (13,987, 8881 women and 5106 men; median age 73). They formed the cohort that was followed up for 6 1/2 years using discharge summaries from three hospitals serving the area and death certificates from the health department. Only 13 respondents were lost to follow up but seemed not to have died. MAIN OUTCOME MEASURES--Incidences of cardiovascular diseases, cancers, gastrointestinal bleeding, ulcers, and cataracts were compared in participants who did and did not take aspirin daily. RESULTS--Age adjusted incidences were computed with an internal standard and five age groups. By 1 January 1988 there had been 25 incident cases of kidney cancer among all participants; 341 incident cases of stroke, 253 of acute myocardial infarction, 220 of ischaemic heart disease, and 317 of other heart disease were reported among respondents without a reported history of angina, myocardial infarction, or stroke. The incidence of kidney cancer was raised among those who took aspirin daily compared with those who did not take it, although the increase was significant only in men (relative risks = 6.3, 95% confidence interval 2.2 to 17, for men and 2.1, 0.53 to 8.5, for women). Those who took aspirin daily showed no increased risk of any other cancer, except colon cancer for both sexes combined (relative risk = 1.5, 1.1 to 2.2). The risk of acute myocardial infarction was reduced slightly among regular users of aspirin in men but not women. The risk of ischaemic heart disease was almost doubled in those who took aspirin daily compared with non-users (relative risks = 1.9, 1.1 to 3.1, for men and 1.7, 1.1 to 2.7, for women). Small, non-significant increased risks of stroke were observed in both sexes. CONCLUSION--The daily use of aspirin increased the risk of kidney cancer and ischaemic heart disease.

Postmenopausal oestrogen treatment and stroke: a prospective study.

STUDY OBJECTIVE--To determine whether post-menopausal oestrogen use affects the risk of dying from stroke. DESIGN--Postal questionnaire survey to elicit details of oestrogen replacement therapy and potential risk modifiers. SETTING--Californian retirement community. PARTICIPANTS--All 22,781 residents of community (white, affluent, well educated) contacted by mail and phone; 13,986 (61%, median age 73) responded, including 8882 women. These formed cohort for mortality follow up, using health department death certification. Only 13 lost to follow up, apparently not deceased, but 34 excluded because no information on oestrogen use. INTERVENTIONS--None. END POINT--Mortality rate from stroke compared in women who did and did not receive oestrogen replacement treatment. MEASUREMENTS AND MAIN RESULTS--Age adjusted mortality rates were computed using internal standard and four age groups. By January 1987 there had been 1019 deaths in the cohort. Twenty out of 4962 women who used oestrogen replacement treatment died from stroke compared with 43 out of 3845 women who did not use oestrogen replacement treatment: relative risk 0.53, 95% confidence interval 0.31 to 0.91. Protection was found in all age groups except the youngest and was unaffected by adjustment for possible confounding factors (hypertension, smoking, alcohol, body mass index, exercise). CONCLUSIONS--Oestrogen replacement treatment protects against death due to stroke.

Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA

BACKGROUND Prostate cancer is a very common disease in more-developed countries, but its cause is largely unknown. It is an androgen-dependent cancer, and androgens have been proposed as having a substantial role in predisposition to the disease. Thus, variations in androgen metabolism genes may affect risk of this disease. METHODS We screened 216 African-American and 172 Hispanic men with prostate cancer, and 261 African-American and 200 Hispanic healthy men (controls), from a large prospective cohort study (the Hawaii-Los Angeles Multiethnic Cohort Study) for a mis-sense substitution in the human prostatic (or type II) steroid 5alpha-reductase (SRD5A2) gene, the product of which controls metabolic activation of testosterone to dihydrotestosterone. This mis-sense substitution results in an alanine residue at codon 49 being replaced with threonine (A49T). We also reconstructed this mutation in the SRD5A2 cDNA, and overexpressed the enzyme in mammalian tissue culture cells. FINDINGS The A49T aminoacid substitution in the SRD5A2 gene increased the risk of clinically significant disease 7.2-fold in African-American men (95% CI=2.17-27.91; p=0.001) and 3.6-fold in Hispanic men (1.09-12.27; p=0.04). The mutant enzyme had a higher in-vitro Vmax than the normal enzyme (9.9 vs 1.9 nmol min(-1) mg(-1)). INTERPRETATION The A49T variant of the SRD5A2 gene may be a significant contributor to the incidence of prostate cancer in African-American and Hispanic men in Los Angeles. We estimate that the population attributable risk due to this aminoacid substitution for clinically significant disease is about 8% in both populations. Increased conversion of testosterone to dihydrotestosterone catalysed by this variant steroid 5alpha-reductase enzyme may be the cause of the increased risk.

Do regular ovulatory cycles increase breast cancer risk

The “estrogen window hypothesis” of the etiology of breast cancer proposes that unopposed estrogen stimulation is the most favorable state for tumor induction and that normal postovulation progesterone secretion reduces susceptibility. The authors believe that epidemiologic and experimental studies suggest rather that the opposite is true, i.e., that breast cancer risk is directly related to the cumulative number of regular ovulatory cycles. Unlike the endometrium, breast tissue mitotic activity is enhanced in the luteal phase of the menstrual cycle. Regular vigorous physical activity is one method of reducing the frequency of ovulatory cycles, and such exercise could markedly reduce a womans lifetime risk of developing breast cancer.

Estrogen replacement therapy and protection from acute myocardial infarction

As part of a longitudinal study of a southern California retirement community begun in June 1981, 8841 women 44 to 101 years old completed a health survey questionnaire. As of January 1, 1987, 1019 deaths had occurred among these women, who had contributed 40,919 years of follow-up. Women who had used estrogen replacement therapy had a relative risk of death due to all causes of 0.80 compared with women who had never used estrogens (p = 0.0005). Much of this reduced mortality rate was due to a marked reduction in the death rate of acute myocardial infarction among users of estrogen (55 deaths) compared with nonusers (94 deaths; relative risk = 0.59, p = 0.002). This lower acute myocardial infarction death rate was maintained even in the presence of other known risk factors for coronary artery disease. There was no substantial effect of dose or duration of estrogen use on risk, but the relatively small number of deaths limited our ability to estimate these effects accurately. Current users (those who were using estrogen at the time of the initial questionnaire) had a relative risk of 0.47 and past users had a risk of 0.62 compared with women who had never used estrogen (p = 0.003 for trend). A reduced hospitalization rate for acute myocardial infarction was similarly observed for estrogen users compared with nonusers (relative risk = 0.72, p = 0.03).

Rapidly rising breast cancer incidence rates among Asian‐American women

In recent years, breast cancer incidence rates have fluctuated over relatively short time spans; examination of these patterns can provide etiologic clues and direction for prevention programs. Asian‐American women are generally considered to be at lower risk of breast cancer than other ethnic groups. However, their rates are typically based on an aggregation of ethnic Asian populations, which may obscure important ethnic differences in risk. Detailed analyses of the trends in ethnic‐specific incidence rates will provide more information than when ethnicities are combined. Los Angeles County, California, the most populous and probably the most ethnically diverse county in the United States, has a large multi‐ethnic Asian‐American population. Trends in invasive female breast cancer incidence were examined using data from the Los Angeles Cancer Surveillance Program, the population‐based cancer registry covering the County. Athough overall breast cancer incidence rates remained stable in the late 1980s and early 1990s, data for the most recent 5‐year period suggest that incidence may again be increasing for Asian‐American and non‐Hispanic white women over age 50 (estimated annual percent change = 6.3%, p < 0.05 and 1.5%, p < 0.05, respectively), although little change has occurred among black and Hispanic women. Invasive breast cancer incidence rates for Asian‐American ethnic groups are heterogeneous and, for most, are increasing. In Los Angeles County, rates for Japanese‐American women have increased rapidly since 1988 and are now approaching rates for non‐Hispanic white women. Rates among Filipinas, who have historically had higher rates than their other Asian‐American counterparts, are not increasing as rapidly as rates for Japanese women, but remain relatively high. Breast cancer risk among women of Japanese and Filipino ancestry is twice that of Chinese and Korean women. Asian women, who commonly have low breast cancer rates in their native countries, typically experience increasing breast cancer incidence after immigrating to the United States. Ethnic‐specific incidence rates show that Japanese‐Americans, the first Asian population to immigrate to Los Angeles County in large numbers and the most acculturated, have experienced a rapid increase in breast cancer incidence. Japanese‐American rates in Los Angeles County may have already surpassed those of non‐Hispanic whites if recent trends have continued unabated.

Evidence of an X-linked or recessive genetic component to prostate cancer risk

We used data from a population-based cohort study of blacks, Hispanics, Japanese and whites to examine the frequency of prevalent prostate and breast cancer by family history status of first-degree relatives (parents and siblings). Independent of race, the age-adjusted relative risk for prevalent prostate cancer in subjects with affected brothers was approximately two times that in subjects with affected fathers (P < 0.00005). No such excess risk for breast cancer was observed among subjects with affected sisters compared to those with affected mothers (age- and race-adjusted relative risk = 1.10, P= 0.34). The magnitude of the relative risk for prostate cancer in sibling-versus parent-affected groups was significantly different from that of the comparable relative risk for breast cancer (P < 0.00005). An excess risk of prostate cancer in men with affected brothers compared to those with affected fathers is consistent with the hypothesis of an X-linked, or recessive, model of inheritance.