Chung-Cheng Hsieh

Objective Pregnancies reduce the risk of ovarian cancer, and among multiparous women, levels of circulating progesterone might be higher during pregnancies with wider birth spacing. We hypothesized that childbirth with wider birth spacing might reduce maternal risk of invasive epithelial ovarian cancer more than births with narrower spacing. Methods We conducted a case–control study nested in a nationwide cohort of Swedish women from 1961 to 2001. We selected five individually age-matched controls for each case of invasive epithelial ovarian cancer, and analysis for the effect of birth spacing was performed for 5,341 cases and 29,047 controls. We applied unconditional logistic regression analyses adjusting for age, ages at childbirth, educational level, area of residence, and gender of offspring. Results Relative risk of invasive epithelial ovarian cancer associated with each one-year increase in average birth spacing is 1.00 (95% CI = 0.98–1.01) among all women and 0.99 (0.98–1.01) among those born before 1935 and less likely to have used oral contraceptives. Further analyses on the biparous and triparous women did not find a consistent association between birth spacing and the risk of ovarian cancer. Conclusions Birth spacing is unlikely to be a major determinant underlying the protective effects of childbirth on ovarian cancer risk.

We examined the relation with birth weight and umbilical cord blood concentrations of haematopoietic stem and progenitor populations in 288 singleton infants. Across the whole range of birth weight, there was a positive relation between birth weight and CD34⁺CD38⁻ cells, with each 500 g increase in birth weight being associated with a 15.5% higher (95% confidence interval: 1.6–31.3%) cell concentration. CD34⁺ and CD34⁺c-kit⁺ cells had J-shaped relations and CFU-GM cells had a U-shaped relation with birth weight. Among newborns with 3000 g birth weights, concentrations of these cells increased with birth weight, while those below 3000 g had higher stem cell concentrations than the reference category of 3000–3499 g. Adjustment for cord blood plasma insulin-like growth factor-1 levels weakened the stem and progenitor cell–birth weight associations. The positive associations between birth weight and stem cell measurements for term newborns with a normal-to-high birth weight support the stem cell burden hypothesis of cancer risk.

Introduction: Prenatal levels of mitogens may influence the lifetime breast cancer risk by driving stem cell proliferation and increasing the number of target cells, and thereby increasing the chance of mutation events that initiate oncogenesis. We examined in umbilical cord blood the correlation of potential breast epithelial mitogens, including hormones and growth factors, with hematopoietic stem cell concentrations serving as surrogates of overall stem cell potential. Methods: We analyzed cord blood samples from 289 deliveries. Levels of hormones and growth factors were correlated with concentrations of stem cell and progenitor populations (CD34⁺ cells, CD34⁺CD38^- cells, CD34⁺c-kit⁺ cells, and granulocyte–macrophage colony-forming units). Changes in stem cell concentration associated with each standard deviation change in mitogens and the associated 95% confidence intervals were calculated from multiple regression analysis. Results: Cord blood plasma levels of insulin-like growth factor-1 (IGF-1) were strongly correlated with all the hematopoietic stem and progenitor concentrations examined (one standard-deviation increase in IGF-1 being associated with a 15–19% increase in stem/progenitor concentrations, all P < 0.02). Estriol and insulin-like growth factor binding protein-3 levels were positively and significantly correlated with some of these cell populations. Sex hormone-binding globulin levels were negatively correlated with these stem/progenitor pools. These relationships were stronger in Caucasians and Hispanics and were weaker or not present in Asian-Americans and African-Americans. Conclusion: Our data support the concept that in utero mitogens may drive the expansion of stem cell populations. The correlations with IGF-1 and estrogen are noteworthy, as both are crucial for mammary gland development.

Epidemiologic evidence shows that the risk of ovarian cancer is decreased following childbirth. We examined the time points when the decreased risk of postpartum maternal ovarian cancer reaches the lowest point and whether the protective effect diminishes over time. A case-control study nested within the Swedish Fertility Register included 10,086 cases of epithelial ovarian cancer recorded in the Swedish Cancer Register from 1961 to 2001. From the Fertility Register, 49,249 eligible subjects matched to the cases by age were selected as controls. The analysis contrasted risk between adjacent parities through logistic regression models that included indicator variables representing each year of age, age at delivery, and time since delivery. Compared with nulliparous women, uniparous women had a transient decrease in maternal ovarian cancer risk at 2 years after delivery (spline-derived odds ratio, 0.71; 95% confidence interval, 0.53-0.95, for those delivered at age 25 years) and maintained a lower risk for 4 years postpartum. Similar transient decreases were observed in biparous women compared with uniparous women and in women with three parities compared with biparous women. The protective effect of childbearing seemed to diminish with time. The transient decrease in postpartum ovarian cancer risk may define the latent period required for pregnancy hormones in clearing out ovarian cells that have undergone early stages of malignant transformation. The period before the risk increases again could indicate the period required for ovarian cancer induction. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2508–13)

Intrauterine and perinatal factors have been linked to risk of childhood leukemia, testicular cancer, and breast cancer in the offspring. The pool of stem cells in target tissue has been suggested as a critical factor linking early life exposures to cancer. We examined the relation between intrauterine hormone levels and measurements of stem cell potential in umbilical cord blood. Cord blood donors were 40 women, ages ≥18 years, who delivered, from August 2002 to June 2003, a singleton birth after a gestation of at least 37 weeks. We assayed plasma concentrations of estradiol, unconjugated estriol, testosterone, progesterone, prolactin, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), and IGF binding protein-3. For stem cell potential, we measured concentrations of CD34+ and CD34+CD38− cells and granulocyte-macrophage colony-forming unit (CFU-GM). We applied linear regression analysis and controlled for maternal and neonatal characteristics. We found strong positive associations between IGF-I and stem cell measures, 1 SD increase in IGF-I being associated with a 41% increase in CD34+ (P = 0.008), a 109% increase in CD34+CD38− (P = 0.005), and a 94% increase in CFU-GM (P = 0.01). Similar associations were observed for IGF binding protein-3. Among steroid hormones, estriol and testosterone were significantly positively associated with CD34+ and CFU-GM. These findings indicate that levels of growth factors and hormones are strongly associated with stem cell potential in human umbilical cord blood and point to a potential mechanism that may mediate the relationship between in utero exposure to hormones and cancer risk in the offspring.

The hypothesis that in utero exposure to pregnancy hormones, notably estrogens, is related to the occurrence of breast cancer in the offspring has been examined in a number of epidemiological and experimental studies. Many studies have provided direct or indirect evidence that supports the hypothesis of an intrauterine component in the origin of breast cancer. Human studies to examine the underlying biological mechanisms, however, have been limited. We review the likely role of stem cells in hormone-mediated carcinogenic process, particularly as intermediate steps between in utero exposure to hormones and breast cancer. We summarize also studies related to the assumptions of the hypothesis concerning in utero exposure. We propose the use of stem cell potential as a measurable variable of the ‘fertile soil’, a term that has been used to characterize the consequences of fetal exposure to intrauterine environment. We conclude by outlining a feasible population-based study that measures stem cell potential to explore mechanisms mediating the relation between in utero exposure to pregnancy hormones and breast cancer risk in the offspring.

The objective of this study is to determine correlates of prolactin and growth hormone levels among pregnant women in the USA and China. We studied 304 pregnant Caucasian and 335 pregnant Chinese women. Levels of prolactin and growth hormone were measured at weeks 16 and 27 of gestation, and correlated with maternal, gestational and perinatal characteristics. Both growth hormone and, to a lesser extent, prolactin were inversely associated with pregnancy weight and body mass index, history of a previous live birth and newborn size, whereas educated women had higher levels of both hormones. Growth hormone levels were lower in women who gained more weight, smoked and had nausea and vomiting during pregnancy, whereas prolactin increased with longer total gestation. We found robust associations between maternal and newborn characteristics on the one hand and prolactin and growth hormone during pregnancy on the other.

During a 4-year period from January 1995 to December 1998, blood samples and questionnaire data were obtained from 333 incident cases of hepatocellular carcinoma (HCC), as well as from 360 controls who were hospitalized for eye, ear, nose, throat or orthopedic conditions in Athens, Greece. Coded sera were tested for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) by third-generation enzyme immunoassays, and information on smoking habits and beverage consumption was obtained. We found a significant dose-response, positive association between smoking and HCC risk [>/= 2 packs per day, odds ratio (OR)=2.5]. This association was stronger in individuals without chronic infection with either HBV or HCV (>/= 2 packs per day, OR=2.8). Consumption of alcoholic beverages above a threshold of 40 glasses per week increased the risk of HCC (OR=1.9). We also found evidence of a strong, statistically significant and apparently super-multiplicative effect of heavy smoking and heavy drinking in the development of HCC (OR for both exposures=9.6). This interaction was particularly evident among individuals without either HBsAg or anti-HCV (OR for both exposures=10.9). Coffee intake was not positively associated with HCC risk, but the reverse could not be excluded for the subgroup of chronically infected individuals. In conclusion, tobacco smoking and heavy alcohol consumption are associated with increased risk of HCC, especially when these 2 exposures occur together.