Bioidentical hormones.

After the results of the Women's Health Initiative trials were published, patient and clinician interest in potential alternatives to conventional hormone therapy (HT) has grown. A commonly used alternative therapy involves custom-compounded steroid hormone preparations, formulated by compounding pharmacies. Many postmenopausal women consider the hormones as natural or bioidentical, in contrast to hormones used in conventional HT, which they consider synthetic. In actuality, the chemical structures of many of the hormones used in bioidentical HT (BHT) are the same as those used in conventional HT. To customize formulations, compounding pharmacies frequently use saliva testing to measure hormones. However, there is a misconception that salivary hormone levels are equivalent to non-protein-bound (free) hormones in blood. Because hormonal custom-compounded formulations are not approved by the Food and Drug Administration (FDA), there are concerns regarding their purity, potency, and quality. Evolving regulatory guidelines by the FDA on oversight of these products should lessen the concerns regarding their safety and efficacy. This review addresses important misconceptions and uncertainties pertaining to BHT, the relationship between salivary and serum/plasma steroid hormone concentrations, the effect of topical progesterone creams on the endometrium, the variability in custom-compounded steroid preparations, and FDA oversight of custom-compounded products.

Circulating androgen levels before and after oophorectomy in premenopausal and postmenopausal women.

OBJECTIVE: This study aimed to determine the effect of oophorectomy on baseline serum levels of androgens and estrogens in premenopausal and postmenopausal women. METHODS: Fourteen premenopausal and 10 postmenopausal women underwent total hysterectomy and bilateral oophorectomy for benign disease of the uterus. Serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), testosterone (T), dihydrotestosterone (DHT), 5α-androstane-3α,17ß-diol-17ß-glucuronide (3α-diol G), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG) were measured by highly specific immunoassays prior to surgery and 2 weeks afterward. Free T and free E2 were calculated. Differences were determined between preoperative (preop) and postoperative (postop) samples, and between premenopausal and postmenopausal women. RESULTS: In premenopausal women, postop levels of total and free T, DHT, and total and free E2 decreased significantly from preop. Postop levels of DHEAS, A, 3α-diol G, and SHBG were decreased, but not significantly different from preop. In postmenopausal women, postop levels of total and free T and total and free E2 decreased significantly from preop, but there was little change in the other compounds. Significant differences in the mean change from baseline between premenopausal and postmenopausal women were observed only for E1 and total and free E2. CONCLUSION: The significant decrease in serum T in postmenopausal women following oophorectomy adds to the evidence that the postmenopausal ovary continues to produce T.

Endogenous sex steroid hormones and glucose in a South-Asian population without diabetes: the Metabolic Syndrome and Atherosclerosis in South-Asians Living in America pilot study.

AIMS: To examine the associations between endogenous sex steroid hormones (oestradiol, testosterone and sex hormone-binding globulin) with diabetes risk in a South-Asian population living in the USA. METHODS: We used data from the Metabolic Syndrome and Atherosclerosis in South-Asians Living in America pilot study. The analytical sample included 60 women and 45 men of Asian Indian origin living in the San Francisco Bay Area, who were free from diabetes and cardiovascular disease and did not use exogenous sex steroids. Sex steroid hormone levels were assessed by validated conventional radioimmunoassays, and visceral and hepatic adiposity were assessed by computed tomography. We used multivariable regression to examine the association between endogenous sex steroid hormone levels (log-transformed) and fasting glucose and 2-h glucose levels in a series of sex-stratified models adjusted for age, waist circumference, visceral and hepatic adiposity, and insulin resistance. RESULTS: In age-adjusted models, lower levels of sex hormone-binding globulin (ß = -0.18, 95% CI -0.30, -0.06) and higher levels of free testosterone (ß = 0.14, 95% CI 0.02, 0.26) were associated with elevated fasting glucose levels in South-Asian women, whereas lower levels of sex hormone-binding globulin (ß = -0.14, 95% CI -0.26, -0.02) and lower levels of total testosterone (ß = -0.12, 95% CI -0.24, 0.00) were associated with elevated fasting glucose levels in South-Asian men. Adjustment for waist circumference, visceral adiposity and insulin resistance attenuated most of these associations, while adjustment for hepatic adiposity strengthened some of the observed associations. Similar results were found for 2-h glucose levels. CONCLUSIONS: Results were consistent with previous research, which suggests that endogenous sex steroid hormones are a risk factor for diabetes across multiple race/ethnic groups. Additional studies are needed to determine whether visceral fat is a mediator or confounder of associations between sex steroid hormone and glucose levels.

Effects of aromatase inhibitors and body mass index on steroid hormone levels in women with early and advanced breast cancer.

BACKGROUND: Aromatase inhibitors (AIs) are central to the management of oestrogen receptor-positive breast cancer in the adjuvant and metastatic setting. Levels of circulating steroid hormones (SHs) were measured in patients established on AIs to investigate: the influence of body mass index (BMI) in both the adjuvant and metastatic setting; the class of AI utilized in the adjuvant setting (steroidal versus non-steroidal); and differences in SH levels between women treated adjuvantly and those receiving a second-line AI for locally advanced/metastatic disease. METHODS: Plasma levels of androstenedione, 5-androstene-3ß,17ß-diol, dehydroepiandrosterone, oestradiol and testosterone were measured by radioimmunoassay in women with breast cancer who were receiving AIs in either an adjuvant or a metastatic setting. Differences between mean SH levels by class of AI, BMI, and second-line versus adjuvant therapy were assessed. RESULTS: Sixty-four women were receiving AI therapy, 45 (70 per cent) in an adjuvant setting and 19 (30 per cent) were taking a second-line AI. There was no significant correlation between BMI and SH levels. However, BMI was significantly higher in the second-line AI cohort compared with the adjuvant cohort (29.8 versus 26.2 kg/m2 respectively; P = 0.026). In the adjuvant setting, patients receiving a steroidal AI had significantly higher levels of all five hormones (P < 0.050). In the second-line AI cohort, oestradiol levels were significantly higher than in the adjuvant cohort (4.5 versus 3.3 pg/ml respectively; P = 0.022). Multivariable analysis adjusted for BMI confirmed the higher residual oestradiol level in the second-line AI group (P = 0.063) and a significantly higher androstenedione level (P = 0.022). CONCLUSION: Residual levels of SH were not significantly influenced by BMI. However, the significant differences in residual SH levels between the second-line and adjuvant AI cohort is of relevance in the context of resistance to AI therapy, and warrants further investigation.

Treatment of postmenopausal women with topical progesterone creams and gels: are they effective?

Topical progesterone creams and gels can be obtained over the counter and/or by prescription from custom-compounding pharmacies and are used by thousands of postmenopausal women for hormonal treatment. However, the effectiveness of these preparations for protecting the endometrium from unopposed estrogen is controversial, due largely to the very low serum progesterone levels that are achieved. Despite these low serum levels, salivary and capillary blood levels are very high and a protective endometrium has been reported in a limited number of studies. Topical alcohol-based, but not water-based, gels appear to yield luteal-phase serum progesterone levels but studies with these preparations are scant. Long-term studies with percutaneous progesterone creams and gels are likely to provide valuable information for treatment of postmenopausal women with this popular route of administration.

Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.

BACKGROUND: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. METHODS: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. FINDINGS: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. INTERPRETATION: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Metabolic syndrome and insulin resistance in relation to biliary tract cancer and stone risks: a population-based study in Shanghai, China.

BACKGROUND: Serum lipids, diabetes, and obesity, individual components of metabolic syndrome, are associated with biliary tract cancer and stone risk, but the associations of metabolic syndrome or insulin resistance with biliary tract cancers and stones are not well studied. METHODS: In this population-based case-control study in Shanghai, China (627 biliary tract cancers, 1037 biliary stones, and 959 controls), metabolic syndrome was defined as the presence of any three of the five components, including high waist circumference, high triglycerides, low high-density lipoprotein cholesterol (HDL), high blood pressure, and diabetes. Insulin resistance and ß-cell function were assessed, using homeostasis assessment models. RESULTS: Metabolic syndrome was significantly associated with gallbladder cancer (odds ratio (OR)=2.75, 95% confidence interval (95% CI)=1.82-4.15) and biliary stones (OR=1.64, 95% CI=1.24-2.16), with a significant dose effect with increasing number of metabolic syndrome components (P trend <0.0001). The observed association persisted among subjects without a history of diabetes. The association between insulin resistance and gallbladder cancer was borderline (P trend=0.06). There was a significant inverse association between ß-cell function and gallbladder cancer risk (P trend <0.001). CONCLUSION: Our findings suggest that metabolic syndrome and insulin resistance have a role in the aetiology of biliary tract cancers and biliary stones, and if confirmed, they imply that lifestyle control of these factors may lower the risk of biliary stones and biliary tract cancer.

Effect of statins on estrogen and androgen levels in postmenopausal women treated with estradiol.

OBJECTIVE: A considerable number of postmenopausal women who receive estrogen therapy are also treated for hypercholesterolemia with cholesterol-lowering statins. Statins and steroid hormones can compete for the same steroid-metabolizing enzymes. We investigated whether long-term administration of statins had an effect on serum estrogen and androgen levels in postmenopausal women receiving and not receiving oral estrogen therapy. METHODS: A subgroup analysis from the Estrogen in the Prevention of Atherosclerosis Trial, a randomized, double-blind, placebo-controlled trial, was performed. A total of 222 women were randomized to receive either placebo or 1 mg of oral micronized 17ß-estradiol daily for 2 years. In both the placebo and treatment groups, participants with low density lipoprotein cholesterol levels >160 mg/dl were treated with statins. Blood samples were obtained at baseline and every 6 months during the trial. Serum levels of dehydroepiandrosterone, androstenedione, testosterone, estrone and 17ß-estradiol were measured by radioimmunoassay. RESULTS: Among 86 placebo- and 90 estradiol-treated subjects with baseline and on-trial hormone measurements, no significant differences were observed between the statin-free and statin-treated groups in mean changes from baseline to on-trial levels in any of the androgens or estrogens, whether or not the postmenopausal women were treated with estrogen. CONCLUSION: The results suggest that estrogen therapy and statins can be used simultaneously with no deleterious effects on circulating hormone levels.

Endometrial effect of progesterone delivered by vaginal rings in estrogen-treated postmenopausal women.

AIM: The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women. METHOD: Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium. RESULTS: Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group. CONCLUSION: The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.

Circulating maternal and umbilical cord steroid hormone and insulin-like growth factor concentrations in twin and singleton pregnancies.

In addition to being associated with a higher risk of complications during pregnancy, twinning may also be a proxy for altered hormonal exposure for mothers and twin offspring, with implications for their health later in life. We compared maternal and fetal steroid hormone and insulin-like growth factor concentrations between singleton (n=62) and twin (n=41) pregnancies. Maternal concentrations of androgens, estrogens, insulin-like growth factor (IGF)-1, IGF-binding protein (BP)-3 and prolactin were quantified during the third trimester and at delivery, as well as in the fetal circulation at birth. Geometric means accounting for gestational age were calculated for hormone concentrations and compared between matched twin and singleton pregnancies. Most maternal hormone concentrations were modestly higher in twin than in singleton pregnancies in the third trimester (ranging from 8.3% for IGF-1 to 17.1% for estradiol) and at delivery (ranging from 11.1% for IGFBP-3 to 15.2% for estriol). Cord serum hormones were generally similar in twin and singleton pregnancies, except for IGFBP-3, which was 200% lower in twins. The modest differences in maternal hormones in late gestation seem unlikely to explain alterations in hormonally related disease risk in mothers of twins compared with singletons. The large deficit of IGFBP-3 in the fetal circulation of twins at birth may allow for sufficient concentrations of IGF-2 for growth and development in an environment of shared nutritional resources.

Serum prostate-specific antigen but not testosterone levels decrease in a randomized soy intervention among men.

BACKGROUND: Low prostate cancer incidence and high soy intake in Asian countries suggest a possible protective effect of soy foods against prostate cancer. The goal of this pilot study was to evaluate the feasibility of a randomized, crossover soy trial among men and to investigate the effects of daily soy intake on serum prostate-specific antigen (PSA) and testosterone levels. METHODS: We randomized 24 men to a high or a low soy diet for 3 months. After a 1-month washout period, the men crossed over to the other treatment. During the high soy diet, the men consumed two daily soy servings; during the low soy diet, they maintained their usual diet. During the entire study each man donated four blood samples and five overnight urine samples. Dietary compliance was assessed by soy calendars, 24-h dietary recalls, and urinary isoflavone excretion measured by high-pressure liquid chromatography with photodiode array detection. Blood samples were analyzed for serum testosterone and PSA by radioimmunoassay. When necessary, variables were log transformed. Two sample t-tests compared the two groups before each study period. Mixed models incorporating the repeated measurements were used to evaluate the effect of the soy diet on urinary isoflavone excretion and serum analytes. RESULTS: Twenty-three men aged 58.7+/-7.2 years completed the study. The compliance with the study regimen was high according to self-reported soy food intake and urinary isoflavone excretion. No significant between-group and within-group differences were detected. During the high soy diet, dietary isoflavone intake and urinary isoflavone excretion increased significantly as compared to the low soy diet. A 14% decline in serum PSA levels (P=0.10), but no change in testosterone (P=0.70), was observed during the high soy diet in contrast to the low soy diet. CONCLUSION: The high adherence as shown by three measures of compliance in this pilot trial demonstrated the feasibility of an intervention based on soy foods among free-living men.

Prostate cancer risk and serum levels of insulin and leptin: a population-based study.

BACKGROUND: In a previous study of Chinese men, we found that men with a higher waist-to-hip ratio (WHR) have a higher prostate cancer risk. Because leptin and insulin are related to body fat distribution, we examined whether leptin and insulin were associated with prostate cancer risk. METHODS: Blood samples were collected from 128 case patients with incident prostate cancer and from 306 healthy control subjects randomly selected from residents of Shanghai, CHINA: Epidemiologic information and anthropometric measurements were collected in personal interviews. Serum leptin, insulin, and sex hormone levels were measured by radioimmunoassay, and insulin-like growth factor-I (IGF-I) was measured by enzyme-linked immunosorbent assay. Multiple logistic regression analyses were used to estimate odds ratios for prostate cancer in relation to serum insulin and leptin levels. All statistical tests were two-sided. RESULTS: After adjustment for body mass index, WHR, IGF-I, and sex hormone levels, higher serum insulin levels were associated with a statistically significantly elevated risk of prostate cancer (P<.001). Men in the highest tertile of insulin levels had a 2.56-fold (95% confidence interval [CI] = 1.38 to 4.75) risk of prostate cancer compared with men in the lowest tertile. Regardless of the tertile level of WHR, higher serum insulin levels were associated with an increased risk of prostate cancer: Men in the highest tertiles of WHR (>0.900) and insulin (>8.83 microU/mL) had 8.55 times (95% CI = 2.80 to 26.10) the prostate cancer risk of men in the lowest tertiles of both, and those in the lowest tertile of WHR (<0.873) and highest tertile of insulin had 4.30 times (95% CI = 1.17 to 15.70) the risk. By contrast, the association between leptin levels and prostate cancer risk was not statistically significant. CONCLUSION: Our results suggest that serum insulin levels may influence the risk of prostate cancer in Chinese men. Further research, especially prospective studies, is needed to confirm these findings in high-risk populations and to clarify the underlying mechanisms involved.

Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women.

BACKGROUND: It has been suggested that women who metabolize a larger proportion of their endogenous estrogen via the 16alpha-hydroxylation pathway may be at elevated risk of breast cancer compared with women who metabolize proportionally more estrogen via the 2-hydroxylation pathway. However, the supporting epidemiologic data are scant. Consequently, we compared the ratio of urinary 2-hydroxyestrone (2-OHE1) to 16alphahydroxyestrone (16alpha-OHE1) in postmenopausal women with breast cancer and in healthy control subjects. METHODS: Estrogen metabolites were measured in urine samples obtained from white women who had participated in a previous population-based, breast cancer case-control study at our institution. All P values are from two-sided tests. RESULTS: All of the urinary estrogens measured, with the exception of estriol, were higher in the 66 case patients than in the 76 control subjects. The mean value of urinary 2-OHE1 in case patients was 13.8% (P = .20) higher than that in control subjects, 16alpha-OHE1 was 12.1% (P = .23) higher, estrone was 20.9% higher (P = .14), and 17beta-estradiol was 12.0% higher (P = .36). The ratio of 2-OHE1 to 16alpha-OHE1 was 1.1% higher in the patients (P = .84), contrary to the hypothesis. Compared with women in the lowest third of the values for the ratio of urinary 2-OHE1 to 16alpha-OHE1, women in the highest third were at a nonstatistically significantly increased risk of breast cancer (odds ratio = 1.13; 95% confidence interval = 0.46-2.78), again contrary to the hypothesis. CONCLUSION: This study does not support the hypothesis that the ratio of the two hydroxylated metabolites (2-OHE1/16alpha-OHE1) is an important risk factor for breast cancer.

Serum hormones and the alcohol-breast cancer association in postmenopausal women.

BACKGROUND: Alcohol ingestion is associated with an increased risk of breast cancer in most epidemiologic studies. Results, however, are heterogeneous at lower levels of alcohol intake, and a biologic mechanism for the association has not been clearly identified. To determine whether alcohol consumption by postmenopausal women elevates serum levels of hormones associated with an increased risk of breast cancer, we performed a controlled feeding study. METHODS: Participants were 51 healthy postmenopausal women not using hormone replacement therapy. Each participant rotated through three 8-week dietary periods in which she consumed 15 or 30 g of alcohol per day or an alcohol-free placebo beverage. The order of assignment to the three alcohol levels was random. During the dietary periods, all food and beverages were supplied by the study, and energy intake was adjusted to keep body weight constant. Levels of estradiol, estrone, estrone sulfate, testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenediol were measured by radioimmunoassays in serum collected at the end of each dietary period. All statistical tests are two-sided. RESULTS: When women consumed 15 or 30 g of alcohol per day, respectively, estrone sulfate concentrations increased by 7.5% (95% confidence interval [CI] = -0.3% to 15.9%; P =.06) and 10.7% (95% CI = 2.7% to 19.3%; P =.009) and DHEAS concentrations increased by 5.1% (95% CI = 1.4% to 9.0%; P =.008) and 7.5% (95% CI = 3.7% to 11.5%; P<.001) relative to levels when women consumed placebo. None of the other hormones measured changed statistically significantly when women consumed alcohol. CONCLUSIONS: Results suggest a possible mechanism by which consumption of one or two alcoholic drinks per day by postmenopausal women could increase their risk of breast cancer.

Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility.

The prostate is an androgen-regulated organ, which has led to long-standing interest in the role of androgens in prostate carcinogenesis. Although evidence of a hormonal etiology for prostate cancer is strong, it is almost entirely circumstantial. Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-specific exposure to endogenous steroid hormones. The international and racial-ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, have suggested that whereas environmental factors are likely to be important, genetic factors might also play a central role in determining prostate cancer risk. We are developing a polygenic model of prostate carcinogenesis focused around a series of genes involved in androgen biosynthesis and androgen activation, transport, and metabolism in the prostate. In this developing model, we have initially targeted four genes based on three main criteria: (a) all encode products that play important roles in inducing androgen stimulation in the prostate; (b) all are polymorphic; and (c) all show substantial allelic variation in the polymorphic marker among the racial-ethnic groups of greatest interest in terms of prostate cancer risk. In addition to studying how the polymorphic markers of interest are related to prostate cancer development within and between racial-ethnic groups, we are concurrently evaluating whether genotypic variations correlate in the anticipated direction with biochemical parameters in vitro and in vivo. We summarize the development of this model and the state of knowledge related to each of the genes comprising the current model. We discuss the extent to which the current model can explain demographic variation in prostate cancer risk as well as the potential for future expansion of the model to incorporate environmental risk factors as well as additional genes. The model, when fully developed, can potentially provide a basis for targeting populations for screening interventions and/or preventive strategies aimed at the multigene products or at the genes themselves.

Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations.

An increased level of serum estrogen is one marker of breast cancer risk. We have recently reported that increased risk of advanced breast cancer is associated with a common allele of the cytochrome P450c17alpha gene (CYP17), designated A2. We now show that CYP17 genotype is associated with serum hormone levels among 83 young, nulliparous women. Serum estradiol (E2) levels measured around day 11 of the menstrual cycle were 11 and 57% higher (P = 0.04), respectively, among women hetero- and homozygous for the CYP17 A2 allele compared to A1/A1 women. Similarly, around cycle day 22, E2 levels were 7 and 28% higher (P = 0.06), and progesterone levels were 24 and 30% higher (P = 0.04), respectively. These data provide direct evidence of genetic control of serum hormone levels.

Do urinary estrogen metabolites reflect the differences in breast cancer risk between Singapore Chinese and United States African-American and white women?

Breast cancer risk is substantially lower in Singapore than in women from the United STATES: Part of the risk discrepancy is probably explained by differences in the production of endogenous estrogens, but differences in the pathway by which estrogen is metabolized may also play a role. We undertook a study to determine whether the ratio of urinary 2-hydroxyestrone (2OHE(1)):16alpha-hydroxyestrone (16alpha-OHE(1)) was higher in Singapore Chinese than in a group of United States (predominantly African-American) women living in Los ANGELES: We also wanted to determine whether any difference in estrogen metabolite ratio between these two groups of women was greater than that in estrone (E(1)), estradiol (E(2)) and estriol (E(3)). The participants in this study were randomly selected healthy, non-estrogen using women participating in the Singapore Chinese Health Study (n = 67) or the Hawaii/Los Angeles Multiethnic Cohort Study (n = 58). After adjusting for age and age at menopause, mean urinary 2-OHE(1) was only 23% (P = 0.03) higher in Singapore Chinese than in United States women, and there were no statistically significant differences in 16alpha-OHE(1) levels or in the ratio of 2-OHE(1):16alpha-OHE(1) between the two groups. The adjusted mean 2-OHE(1):16alpha-OHE(1) ratio was 1.63 in Singapore Chinese and 1.48 in United States women (P = 0.41). In contrast, the adjusted mean values of E1, E2, and E3 were 162% (P < 0.0001), 152% (P < 0.0001), and 92% (P = 0.0009) higher, respectively, in United States women than in Singapore Chinese women. Our study suggests that urinary E1, E2, and E3 reflect the differences in breast cancer risk between Singapore Chinese and United States women to a stronger degree than the estrogen metabolites 2OHE(1) and 16alpha-OHE(1) or the ratio of 2OHE(1):16alpha-OHE(1.)

A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase.

Prostate cancer is the most common serious cancer diagnosed in men in the United States. This disease is also characterized by a striking racial/ethnic variation in incidence: highest in African-Americans, intermediate in Caucasians, slightly lower in Latinos, and lowest in Asians. Ample biochemical and epidemiological evidence suggests a role for androgens, particularly testosterone and dihydrotestosterone, in prostate cancer etiology. We have analyzed a candidate gene for prostate cancer, SRD5A2, encoding prostatic steroid 5alpha-reductase type II, which converts testosterone into the more bioactive dihydrotestosterone, for mutations. We report here one amino acid substitution, V89L, which replaces valine at codon 89 with leucine. This substitution is a "germline" (constitutional) DNA polymorphism, and it is common, panethnic, and reduces in vivo steroid 5alpha-reductase activity. This substitution is particularly common among Asians and may explain the low risk for prostate cancer in this population.

Aromatase and breast cancer susceptibility.

Based on experimental and epidemiological evidence it is hypothesized that estrogen increases breast cancer risk by increasing mitotic activity in breast epithelial cells. Aromatase is crucial to the biosynthesis of estrogens and may therefore play a role in breast cancer development. Supporting data for an etiological role of aromatase in breast tumor biology are several-fold. First, the association between weight and postmenopausal breast cancer risk may be mediated by aromatase. Secondly, a pilot study found a higher aromatase expression in normal breast adipose tissue from breast cancer cases as opposed to healthy women. Thirdly, experimental data in animals suggest that aromatase activity predisposes mammary tissue to preneoplastic and neoplastic changes. In a multiethnic cohort study conducted in Los Angeles and on Hawaii we investigated (i) whether the plasma estrone to androstenedione (E1/A) ratio in different ethnic groups was associated with ethnic differences in breast cancer incidence, and (ii) whether genetic variation in the CYP19 gene encoding the P450 aromatase protein was associated with breast cancer risk. The age- and weight-adjusted ethnic specific E1/A ratios x 100 among women without oophorectomy were 7.92 in African-Americans, 8.22 in Japanese, 10.73 in Latinas and 9.29 in non-Latina Whites (P=0.09). The high E1/A ratio in Latina women was not associated with a high breast cancer incidence; in fact Latina women had the lowest breast cancer incidence in the cohort observed so far. We found no consistent association of an intronic (TTTA)n repeat polymorphism with breast cancer risk in different ethnic groups. This polymorphism was not associated with differences in the plasma E1/A ratio in a way that would predict its functional relevance. We describe a newly identified TTC deletion in intron 5 of the CYP19 gene that is associated with the (TTTA)n repeat polymorphism. Neither this polymorphism, nor a polymorphism at codon 264 in exon VII of the CYP19 gene, was associated with breast cancer. We did not identify any genetic variation in exon VIII in 54 African-American subjects. We identified rare genetic variants of unknown functional relevance in the promoter 1.4 of the CYP19 gene in 3 out of 24 Latina women. Further investigation into the role of aromatase in breast cancer etiology is important, given that the potential use of aromatase inhibitors as breast cancer chemopreventives depends on these results.