Abstract
Objectives
Among women attending antenatal clinics during 1934–1944 a large intercristal diameter, the maximum distance between the pelvic iliac crests, was associated with a raised incidence of breast and ovarian cancer in the daughters in later life. At puberty, the intercristal diameter of girls enlarges rapidly under the influence of estrogen. We speculated that high maternal estrogen concentrations during pregnancy initiate hormonal cancers in their daughters. Here, we examine the association between the mothers’ intercristal diameters and prostate cancer in their sons.
Methods
Using the national cancer registry we identified 221 cases of prostate cancer among 6,975 men born during 1934–1944 in Helsinki, Finland. Four thousand four hundred and one of these men had their mother’s bony pelvic measurements recorded: there were 149 cases among them.
Results
Hazard ratios for prostate cancer rose as the mother’s intercristal diameter increased; but this association was restricted to men who were born before 40 weeks of gestation. Among these men the hazard ratio was 1.27 (95% CI 1.09–1.48; P = 0.002). The hazard ratio was 2.2 (1.3–3.7; P < 0.001) in men whose mothers weighed more than 80 kg in late pregnancy compared with those whose mothers weighed 60 kg or less.
Conclusions
These findings are consistent with a conceptual framework for the origins of hormonally dependent cancers that invokes exposure of embryonic tissue to maternal sex hormones followed by resetting of the fetal hypothalamic-gonadotropin axis in late gestation. We hypothesize that compensatory prepubertal growth among girls is associated with hormonal cancers in the next generation.
The pubertal growth of girls is characterized by broadening of the hips in anticipation of childbirth. The intercristal diameter, the maximal distance between the iliac crests, increases rapidly under the control of estrogens (Ellison, 1998; Tanner, 1962). The interspinous diameter, the distance between the anterior-superior iliac spines, increases less rapidly so that the iliac crest becomes rounder. We have suggested that a large intercristal diameter reflects high circulating concentrations of estrogens at puberty that persist through reproductive life. In a previous study of women born in Helsinki, Finland we found that the incidence of breast cancer was higher in those whose mothers had a large intercristal diameter and a large intercristal-interspinous difference (Barker et al., 2008b). We speculated that, if a female embryo is exposed to high maternal estrogen concentrations, this would produce genetic instability in differentiating breast and ovarian cells and thereby initiate cancer. Catechol estrogen, a metabolite of estradiol, is thought to cause chromosomal instability by breaking DNA strands (Yoshi and Ohshima, 1998; Yue et al., 2003). The literature linking estrogen to breast cancer is specific to the individual who develops cancer and not, as in our studies, the effects on the offspring. The associations between the mother’s intercristal diameter and breast cancer were strongest in women who were born at or after 40 weeks of gestation. We speculated that prolonged exposure to placental estrogens permanently reset the fetal hypothalamic gonadotropic axis.
In contrast to the findings for breast cancer, the mother’s of women who developed ovarian cancer were characterized by large intercristal and intertrochanteric diameters, the distance between the greater trochanters (Barker et al., 2008a). At puberty, the intratrochanteric diameter increases at a similar rate in boys and girls and is controlled by growth hormone and androgens. Ovarian cancer may therefore be initiated by a more masculine hormonal profile than that which initiates breast cancer. These findings raise the possibility that prostate cancer, the commonest hormonally dependent cancer in men, may also be initiated by exposure to maternal or placental sex hormones during gestation. We have examined the effects of mothers’ pelvic diameters on prostate cancer among men in the Helsinki Birth Cohort. Because there is evidence that prostate cancer is associated with raised testosterone concentrations in adults (Jung et al., 2011; Rahman et al., 2011), we hypothesized that prostate cancer would be commoner in the sons of women with broad hips, as measured by the intertrochanteric diameter.
METHODS
The study cohort comprised 6,975 men born from 1934 to 1944 in one of the two maternity hospitals in Helsinki, the University Central Hospital, and the City Maternity Hospital. Details of the birth records have been described (Eriksson et al., 2001). They include the body size of the baby at birth, the length of gestation estimated from the date of the mother’s last menstrual period, and the mother’s height, weight in late pregnancy, age, parity, and age at menarche. Four thousand four hundred and one (63%) of them include measurements of the bony pelvis. These were used to assess the likelihood of obstructed labor (Anderson, 1930; Berkeley, 1941). Mothers whose records included pelvic measurements tended to be younger and more of them were primiparous, and they were 0.6 cm shorter (P < 0.001). There were two measurements of the distance between the iliac crests, the intercristal diameter, the maximal distance between the iliac crests, and the interspinous diameter, the distance between the anterior-superior iliac spines. The difference between the intercristal and interspinous diameters is used as an index of the roundness of the iliac crest. The intertrochanteric diameter, the distance between the greater trochanters, measures the width of the lower hips. The external conjugate diameter is the distance between the front of the pubic bone and the spine of the fifth lumbar vertebra.
The birth records included data on the father’s occupation, which was grouped into upper and lower middle class and manual workers, based on a classification from Statistics Finland (Barker et al., 2001). The men’s own occupations, recorded at the 1980 census, were obtained through Statistics Finland who grouped them into four classes: higher official, lower official, self-employed, and manual worker. In Finland, cases of cancer are recorded in the national cancer registry. We ascertained all registrations for prostate cancer during 1971 to 2006. Prostate cancer was defined by International Classification of Disease code 185 in revisions 8 and 9 and by code C61 in revision 10. The ethics committee at the National Public Health Institute in Helsinki approved the study.
Statistical methods
The end for our survival analysis was registration with prostate cancer. Men were censored in the analysis when they migrated from Finland, died from causes other than prostate cancer, or reached the end of 2006. We used a Cox proportional hazards model to calculate the hazard ratios for prostate cancer in relation to maternal characteristics and length of gestation. The measurements of mother’s height, weight, pelvic size, age at menarche, and the length of gestation were analyzed as continuous variables although presented in the tables as groups.
RESULTS
The cohort comprised 6,975 men. Two hundred twenty-one of them had had prostate cancer, five of whom had died from the disease. For 149 of the men with prostate cancer, there were measurements of the mother’s pelvic bones. Characteristics of the mothers and their sons are shown in Table 1. The mothers’ pelvic diameters correlated with their heights and weights, the correlation coefficient for the intercristal diameter and weight being 0.47.
TABLE 1.
Numbers and types of measurements made on mothers and sons
| Numbers | Mean | SD | |
|---|---|---|---|
| Mothers | |||
| Age at menarche (years) | 6,760 | 14.7 | 1.7 |
| Age at delivery (years) | 6,970 | 28.3 | 5.4 |
| Height (cm) | 6,385 | 159.8 | 5.7 |
| Weight (kg) | 6,305 | 67.0 | 8.2 |
| Body mass index (kg/m2) | 6,279 | 26.2 | 2.9 |
| Parity | 6,973 | 1.9 | 1.3 |
| Intercristal (cm) | 4,393 | 28.4 | 1.5 |
| Interspinous (cm) | 4,396 | 25.8 | 1.5 |
| Intercristal-interspinous (cm) | 4,393 | 2.5 | 1.1 |
| Intertrochanteric (cm) | 4,380 | 31.3 | 1.6 |
| External conjugate (cm) | 4,380 | 19.4 | 1.1 |
| Sons | |||
| Length of gestation (days) | 6,707 | 279 | 13 |
| Age at prostate cancer (years) | 221 | 61 | 3 |
Body size at birth
Prostate cancer was not associated with birthweight, birth length, or head circumference at birth, with or without allowance for the length of gestation.
Mother’s body size
Table 2 shows hazard ratios for prostate cancer in relation to mother’s height and weight and the three measurements of hip width. There was no trend in hazard ratios with mother’s height but the ratios increased with mother’s weight in late pregnancy and with her body mass index (P = 0.005). Hazard ratios tended to increase with the intercristal, the interspinous, and the intertrochanteric diameters, although none of the trends was statistically significant. Men whose mothers had intercristal diameters greater than 29.5 cm were at significantly increased risk (Table 2). Neither the intercristal-interspinous difference nor the external conjugate diameter was associated with prostate cancer.
TABLE 2.
Hazard ratios for prostate cancer according to mothers’ heights, weights, and pelvic diameters
| Hazard ratio | 95% CI | No. of cases | No. of men | |
|---|---|---|---|---|
| Mother’s height (cm) | ||||
| ≤156.0 | 1.0 | Baseline | 57 | 1,814 |
| 156.1 – 160.0 | 0.8 | 0.6–1.2 | 47 | 1,722 |
| 160.1 – 164.0 | 1.2 | 0.8–1.7 | 55 | 1,524 |
| >164.0 | 1.3 | 0.9–1.8 | 52 | 1,325 |
| P for trend | 0.11 | |||
| Mother’s weight (kg) | ||||
| ≤60.0 | 1.0 | Baseline | 41 | 1,321 |
| 60.1 – 70.0 | 0.9 | 0.6–1.4 | 88 | 3,079 |
| 70.1 – 80.0 | 1.2 | 0.8–1.8 | 56 | 1,548 |
| >80.0 | 2.2 | 1.3–3.7 | 24 | 357 |
| P for trend | <0.001 | |||
| Intercristal diameter (cm) | ||||
| ≤27.5 | 1.0 | Baseline | 42 | 1,331 |
| 27.6 – 28.5 | 0.9 | 0.5–1.4 | 31 | 1,199 |
| 28.6 – 29.5 | 1.0 | 0.6–1.5 | 32 | 1,064 |
| >29.5 | 1.7 | 1.1–2.5 | 44 | 799 |
| P for trend | 0.08 | |||
| Interspinous diameter (cm) | ||||
| ≤25.0 | 1.0 | Baseline | 48 | 1,635 |
| 25.1 – 26.0 | 1.2 | 0.7–1.8 | 37 | 1,206 |
| 26.1 – 27.0 | 1.4 | 0.9–2.2 | 38 | 940 |
| >27.0 | 1.4 | 0.8–2.2 | 26 | 615 |
| P for trend | 0.13 | |||
| Intertrochanteric diameter (cm) | ||||
| ≤30.5 | 1.0 | Baseline | 46 | 1,456 |
| 30.6 – 31.5 | 1.5 | 1.0–2.2 | 50 | 1,168 |
| 31.6 – 32.5 | 0.8 | 0.5–1.3 | 22 | 958 |
| >32.5 | 1.3 | 0.8–2.0 | 31 | 798 |
| P for trend | 0.13 | |||
Length of gestation
There was an inverted U-shaped association between the length of gestation and later prostate cancer (P for quadratic trend 0.04). The highest risk was among men born at 38 weeks. In Table 3, the men are divided around the median gestation period of 40 weeks, the same division used in our previous analyses of breast cancer (Barker et al., 2008b). Among men born before 40 weeks of gestation high mother’s weight and large intercristal and interspinous diameters were associated with high hazard ratios for prostate cancer. The trend with mother’s weight, however, was no longer statistically significant in simultaneous regressions with either of the two pelvic diameters, whose trends remained significant (P = 0.02 for both). These trends are shown in Table 4. Among men born at or after 40 weeks hazard ratios for prostate cancer rose with increasing mother’s weight, but there were no trends with the two diameters (Tables 3 and 4). There were no statistically significant trends with mother’s height, intertrochanteric or external conjugate diameters, or intercristal-interspinous difference in either gestation group.
TABLE 3.
Hazard ratios (HR) for prostate cancer according to mothers’ heights, weights, and pelvic diameters and the length of gestation
| Maternal measurements | Length of gestation (weeks)
|
P for interaction | |||||
|---|---|---|---|---|---|---|---|
| <40
|
≥40
|
||||||
| HR | 95% CI | P-value | HR | 95% CI | P-value | ||
| Height (cm) | 1.02 | 0.98–1.05 | 0.28 | 1.02 | 0.98–1.05 | 0.31 | 0.84 |
| Weight (kg) | 1.02 | 1.00–1.05 | 0.03 | 1.03 | 1.00–1.05 | 0.02 | 0.73 |
| Intercristal (cm) | 1.27 | 1.09–1.48 | 0.002 | 0.95 | 0.82–1.11 | 0.51 | 0.02 |
| Interspinous (cm) | 1.28 | 1.10–1.49 | 0.001 | 0.90 | 0.78–1.05 | 0.18 | 0.002 |
| Intertrochanteric (cm) | 1.12 | 0.96–1.30 | 0.15 | 1.05 | 0.91–1.21 | 0.54 | 0.52 |
TABLE 4.
Hazard ratios for prostate cancer according to mothers’ weights and pelvic diameters and the length of gestation
| Maternal measurements | Length of gestation (weeks)
|
|||||||
|---|---|---|---|---|---|---|---|---|
| <40
|
≥40
|
|||||||
| Hazard ratio | 95% CI | No of cases | No of men | Hazard ratio | 95% CI | No of cases | No of men | |
| Weight (kg) | ||||||||
| ≤60.0 | 1.0 | Baseline | 21 | 694 | 1.0 | Baseline | 17 | 555 |
| 60.1–70.0 | 1.1 | 0.7–1.9 | 49 | 1,456 | 0.7 | 0.4–1.3 | 36 | 1,504 |
| 70.1–80.0 | 1.5 | 0.9–2.7 | 29 | 667 | 0.9 | 0.5–1.7 | 27 | 844 |
| >80.0 | 2.0 | 0.9–4.7 | 8 | 129 | 2.0 | 1.0–4.0 | 16 | 220 |
| P for trend | 0.03 | 0.02 | ||||||
| Intercristal diameter (cm) | ||||||||
| ≤27.5 | 1.0 | Baseline | 14 | 632 | 1.0 | Baseline | 24 | 617 |
| 27.6–28.5 | 1.5 | 0.7–3.2 | 16 | 528 | 0.6 | 0.3–1.1 | 15 | 628 |
| 28.6–29.5 | 1.8 | 0.9–3.7 | 17 | 473 | 0.6 | 0.3–1.1 | 14 | 556 |
| >29.5 | 3.0 | 1.5–5.9 | 23 | 355 | 1.0 | 0.5–1.8 | 20 | 413 |
| P for trend | 0.002 | 0.51 | ||||||
| Interspinous diameter (cm) | ||||||||
| ≤25.0 | 1.0 | Baseline | 16 | 769 | 1.0 | Baseline | 30 | 776 |
| 25.1–26.0 | 2.3 | 1.2–4.5 | 22 | 557 | 0.5 | 0.3–1.0 | 12 | 606 |
| 26.1–27.0 | 2.4 | 1.2–4.7 | 19 | 407 | 1.0 | 0.5–1.7 | 19 | 497 |
| >27.0 | 2.5 | 1.2–5.1 | 13 | 255 | 0.8 | 0.4–1.5 | 12 | 338 |
| P for trend | 0.001 | 0.18 | ||||||
Mother’s age, parity, and age at menarche
Mother’s age, parity, and age at menarche were not related to prostate cancer. The associations between prostate cancer and the mothers intercristal and interspinous diameters were similar in men born to primiparous and multiparous mothers, and in men whose mother’s menarche was early or late, defined by the median age of 14 years.
Socioeconomic status
Prostate cancer was not associated with the socioeconomic status of the family, as indicated by the father’s occupation at the time of the birth. It was, however, associated with the men’s own socioeconomic status, defined by their occupations. Higher socioeconomic status was associated with higher hazard ratios for prostate cancer (P = 0.03). The trends in prostate cancer within the two gestation groups (Tables 3 and 4) were not changed by allowance for socioeconomic status.
DISCUSSION
We have found that men whose mothers had large intercristal and interspinous diameters of the bony pelvis were at increased risk of prostate cancer if they were born before 40 weeks of gestation. Contrary to our hypothesis, prostate cancer was not associated with the mother’s intertrochanteric diameter. The skeletal growth of girls at puberty is characterized by rapid expansion of the intercristal and interspinous diameters under the influence of sex hormones, importantly estrogen (Ellison, 1998; Tanner, 1962). The intratrochanteric diameter expands at a similar rate in boys and girls and is controlled by growth hormone and androgens. We have suggested that the sex hormone profile established in a girl at puberty may persist through her reproductive life, and could initiate breast and ovarian cancers in her daughters during early gestation when the breast and ovarian stem cells are developed (Barker et al., 2008a,b). High catechol estrogen concentrations in the maternal circulation at that time could produce genetic instability in breast and ovarian progenitor cells (Barker et al., 2008a,b; Yoshie and Ohshima, 1998; Yue et al., 2003). This could make the cells vulnerable to cancer in later life. Because ovarian cancer is related to the intertrochanteric diameter as well as the intercristal, and is not related to the intercristal-interspinous difference, we speculated that it is initiated by a more masculine hormonal profile than that which initiates breast cancer (Barker et al., 2008a).
Our present findings suggest that similar processes could initiate prostate cancer and that it is the estrogenic component of the mother’s sex hormone profile rather than the androgenic component. This conclusion is strengthened by the association between high maternal weight in pregnancy and prostate cancer. Greater maternal fat mass is associated with higher circulating estrogen concentrations. There is evidence that men with prostatic cancer have raised testosterone concentrations (Jung et al., 2011; Rahman et al., 2011). This evidence comes from studies of men’s second to fourth digit ratios and is difficult to reconcile with our observations implicating the mother’s estrogen concentrations.
We found that there was an inverted U-shaped association between prostate cancer and the length of gestation, such that the highest risk was in men born at 38 weeks. We suggest that this association reflects altered hypothalamic-gonadotropin settings in the fetus in late gestation. Observations in animals provide strong evidence that lifelong patterns of gonadotropic hormone release are initiated at early development (Barraclough and Gorski, 1961). Among premenopausal women in Sheffield, UK, plasma luteinizing hormone concentrations were raised in those born after 40 weeks of gestation (Cresswell et al., 1997). We have previously shown that the relationship between the intercristal diameter and breast cancer was strongest in women born at or after 40 weeks, and we speculated that this reflected prolonged fetal exposure to placental estrogens with resetting of the hypothalamic-gonadotropic axis (Barker et al., 2008b). For prostate cancer, however, a large intercristal diameter increased the risk only among men born before term. We cannot explain this but speculate that it is also linked to fetal exposure to placental estrogens with resetting of the hypothalamic-gonadotropic axis.
The three common hormonal cancers are associated with a similar maternal phenotype though there are differences in detail. Mothers whose daughters developed breast cancer had large intercristal diameters and a large difference between the intercristal and interspinous diameters so that the iliac crest was round (Barker et al., 2008b). The mothers were of similar stature to all mothers in the cohort, but had had a larger pubertal growth spurt, as indicated by their large intercristal diameter. Because the large pubertal growth spurt did not result in tall adult stature we suggested that it was the result of accelerated prepubertal growth following growth faltering in early childhood (Proos et al., 1993). Further evidence supporting this concept came from the studies of ovarian cancer (Barker et al., 2008a). Broad hips only predicted ovarian cancer in the daughters of mothers with below average stature (160 cm or less) and below average age at menarche (14 years or less). An early onset of menstruation and short adult stature occurs when girls are undernourished and grow slowly in the first few years of life and then are well nourished and catch up in size (Proos et al., 1993). Mothers whose sons later developed prostate cancer were similar to those whose daughters developed breast cancer or ovarian cancer in that they had large intercristal diameters but were similar in stature to all mothers in the cohort. We suggest that, similarly to the mothers whose daughters developed breast or ovarian cancer, the mothers’ large pubertal growth spurts resulted from accelerated prepubertal growth after growth faltering in early childhood.
The ability to mount accelerated “compensatory” growth after growth faltering is common in animals and familiar to farmers (Metcalfe and Monaghan, 2001). In animals compensatory growth has a wide range of physiological and metabolic costs that include premature death. We hypothesize that compensatory growth in girls is associated with an altered sex hormone profile that is established at puberty and persists through reproductive life. This profile predisposes their offspring to hormonal cancers. In children, compensatory growth becomes more common when societies transition from chronic malnutrition to western nutrition. Our hypothesis is consistent with the rise of hormonal cancers in western countries during the past century.
Limitations of the study
The measurements in our study were made during routine obstetric practice 70 years ago. There were no routine checks of the quality of the measurements, just as there are no routine checks of the quality of blood pressure and other measurements made in current clinical practice. Measurement errors would tend to diminish the associations between the pelvic diameters and prostate cancer in later life. The people in our study may not be representative of all people now living in Helsinki, although at birth their social class distribution was similar to that in the city as a whole.
CONCLUSION
These findings are consistent with a conceptual framework for the origins of hormonally dependent cancers that invokes exposure of embryonic tissue to maternal sex hormones followed by resetting of the fetal hypothalamic-gonadotropin axis in late gestation. We hypothesize that rapid compensatory growth among prepubertal girls is associated with an altered sex hormone profile that is established at puberty and persists through reproductive life. This profile predisposes their male and female offspring to hormonal cancers.
Acknowledgments
Contract grant sponsor: Academy of Finland; Contract grant sponsor: British Heart Foundation; Contract grant sponsor: Finnish Diabetes Foundation; Contract grant sponsor: Finnish Foundation for Cardiovascular Research; Contract grant sponsor: Finnish Medical Society Duodecim; Contract grant sponsor: Finska Lđkaresđllskapet; Contract grant sponsor: Foundation for Pediatric Research; Contract grant sponsor: Jalmari and Rauha Ahokas Foundation; Contract grant sponsor: Novo Nordisk Foundation; Contract grant sponsor: Pđivikki and Sakari Sohlberg Foundation; Contract grant sponsor: Signe and Ane Gyllenberg Foundation; Contract grant sponsor: the Royal Society; Contract grant sponsor: Yrj— Jahnsson Foundation; Contract grant sponsor: M. Lowell Edwards Endowment.
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