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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

Cover of Holland-Frei Cancer Medicine

Holland-Frei Cancer Medicine. 5th edition.

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Chapter 13Hormones and the Etiology of Cancer

, MD, , PhD, and , MD.

Substantial and convincing bodies of experimental, clinical, and epidemiologic evidence indicate that hormones play a major role in the etiology of several human cancers. The concept that hormones can increase the incidence of neoplasia was first proposed by Bittner,1 on the basis of experimental studies of estrogens and mammary cancer in mice. This theory has been refined into epidemiologic hypotheses related to cancers of the breast, endometrium, prostate, ovary, thyroid, bone, and testis.2,3 The underlying mechanism proposed for all of these cancers is that neoplasia is the consequence of prolonged hormonal stimulation of the particular target organ, the normal growth and function of which is controlled by one or more steroid or polypeptide hormones. Evidence is mounting to show that the amount of hormone to which a tissue is effectively exposed is under strong genetic control.4 Therefore, in addition to external factors such as diet or exogenous hormone use which may modify hormone profiles, polymorphisms in genes encoding proteins involved in steroid-hormone biosynthesis, metabolism or extra- and intracellular transport, and DNA binding are important determinants of individual cancer risk.4,5

The major carcinogenic consequence of this hormonal exposure at the end organ is cellular proliferation. The emergence of a malignant phenotype depends on a series of somatic mutations that occur during cell division but the entire sequence of genes involved in progression from normal cell to a particular malignant phenotype are not known (Fig. 13.1). Candidate genes include those in the endocrine pathway 4,5 as well as DNA repair genes, tumor suppressor genes, and oncogenes.6–8 Germline mutations have been described in two such tumor suppressor genes, BRCA1 and BRCA2, that have been associated with susceptibility to breast cancer in certain kindreds.9,10 Germline mutations in TP53 are also associated in certain kindreds with an increased risk of breast cancer.11 However, mutations in these genes do not appear to be involved in the majority of sporadic breast cancer. The HER2/neu oncogene is overexpressed in advanced breast cancer, is associated with poor prognosis, and probably represents one critical event in the latter part of breast cancer progression.12

Figure 13.1. Estradiol and, to a lesser degree, other steroid hormones (e.

Figure 13.1

Estradiol and, to a lesser degree, other steroid hormones (e.g., progesterone) drive breast cell proliferation which facilitates mutation or enhances fixation of mutations or facilitates expression of genetic errors by loss of heterozygosity by defects (more...)

Neoplasia of hormone-responsive tissues currently accounts for more than 35% of all newly diagnosed male and more than 40% of all newly diagnosed female cancers in the United States. Given that endogenous hormones apparently affect the risk of these cancers and their overall frequency, concern exists about the effects on cancer risk if the same or closely related hormones are administered for therapeutic purposes (e.g., as contraceptives, as hormone replacement therapy, or for the prevention of miscarriage).13 This chapter provides a review of the epidemiologic and endocrinologic evidence for the role of hormones in the development of specific cancers as well as the current status of the relationship between exogenous hormones and cancers of the breast, endometrium, and ovary.

Breast Cancer

Breast cancer is the most common cancer in women and accounted for approximately 176,300 new cancer diagnoses and 43,700 deaths in 1999.14 Available evidence regarding the hormonal etiology of breast cancer is most consistent with the hypothesis that estrogen is the primary stimulant for breast cell proliferation.2,3 The simultaneous presence of progesterone probably further increases the rate of proliferation.15 This latter conclusion is based largely on the fact that breast mitotic activity peaks during the luteal phase of the menstrual cycle.16

The most consistently documented, hormonally related risk factors for breast cancer are early age at menarche, late age at menopause, late age at first full-term pregnancy, and weight (Table 13.1).17 The age incidence curve for breast cancer emphasizes the importance of ovulation in determining risk.13 The initial cases occur during early adulthood, and the rate of increase in incidence then rises sharply with age until the time of menopause, when it slows dramatically. The rate of increase in the postmenopausal period is approximately only one-sixth the rate of increase in the premenopausal period. This age incidence curve appears, then, to be shaped in a major way by the effects of ovarian activity. Therefore, it is critical to understand the determinants, both genetic and environmental, of the onset, regularity, and cessation of ovulation in order to continue to develop effective prevention modalities for breast cancer.

Table 13.1. A Summary of Established Hormonal Risk and Protective Factors for Breast Cancer.

Table 13.1

A Summary of Established Hormonal Risk and Protective Factors for Breast Cancer.

Reproductive Factors

Early age at menarche is an established risk factor for breast cancer.17 In general, risk decreases approximately 20% for each year that menarche is delayed and this relationship may be further modified by the age at onset of regular ovulatory menstrual cycles. In a study of young women, Henderson and colleagues18 recorded both age at onset of menstruation and the age when “regular” (i.e., predictable) menstruation was first established. For a fixed age at menarche, the establishment of regular menstrual cycles within 1 year of the first menstrual period more than doubled the risk of breast cancer compared with women with a 5-year or longer delay in establishing regular menses. Women with early menarche (i.e., age 12 years or younger) and rapid establishment of regular cycles had an almost four-fold increased risk of breast cancer when compared with women with late menarche (i.e., age 13 years or older) and long duration of irregular cycles.

These observations suggest that regular ovulatory cycles increase a woman’s risk of breast cancer,19 and they support results from an earlier study comparing circulating hormone levels in daughters of women with breast cancer with those in age-matched daughters of controls.20 Daughters of women with breast cancer, who as a group have at least twice the risk of the general population, have higher levels of circulating estrogen and progesterone than found in controls.

Twin studies have suggested a major genetic component to the onset of menarche.21 A polymorphism in the CYP17 gene has been associated with an earlier menarche as well as higher levels of circulating estradiol and progesterone.22 This observation suggests that the CYP17 gene is one of the key genes affecting the onset and quality of ovulation. The relationship between this gene and other genes affecting the steroid biosynthesis pathway is shown in Fig. 13.2. In addition to CYP17, CYP19 (the aromatase gene) and 17HSDB1 are important in estradiol biosynthesis (see Fig. 13.2). Investigations are ongoing evaluating polymorphisms (e.g., single nucleotide base substitutions [SNPs], nucleotide repeats) in these genes, as they may relate to breast cancer risk by their impact on the amount of bioavailable estradiol available to breast tissue (Table 13.2).4

Figure 13.2. Schematic presentation of estrogen metabolism in the ovaries and breast epithelium and four candidate genes that may play a role in breast cancer etiology.

Figure 13.2

Schematic presentation of estrogen metabolism in the ovaries and breast epithelium and four candidate genes that may play a role in breast cancer etiology. The genes of interest are the cytochrome P450c17α (CYP17) gene, the aromatase cytochrome (more...)

Table 13.2. Candidate Genes in Hormone-Related Cancers.

Table 13.2

Candidate Genes in Hormone-Related Cancers.

Although menarche and the onset of ovulation are to some extent genetically determined, it is also critical to establish behaviors that may alter the cumulative number of lifetime ovulatory cycles. Strenuous physical activity may delay menarche. Adolescent girls who engage in regular ballet dancing, swimming or running experience a considerable delay in the onset of menses.23 For example, in one study, ballet dancers had a mean age at menarche of 15.4 years, compared with 12.5 years for controls. Breast development also was delayed in these dancers, and they experienced intermittent amenorrhea throughout their teenage years as long as they remained active dancers. Even moderate physical activity during adolescence can lead to anovular cycles. Girls who engaged in regular, moderate physical activity (averaging at least 600 Kcal of energy expended per week) were 2.9 times more likely than girls who engaged in lesser amounts of physical activity to be anovular.24 More recently, Bernstein and colleagues25 reported that lifetime patterns of leisure-time exercise activity significantly impact the risk of breast cancer in both young women (< 40 years of age) and older, postmenopausal women (55–64 years of age).26 Although many studies have now demonstrated a reduction in breast cancer risk associated with increasing amounts of exercise activity, some have not.27 The inconsistency is likely due to the complexities of collecting information on exercise patterns.28

In the same way that early onset of menarche and regular ovulation equate with a greater cumulative lifetime exposure to estrogen and risk of breast cancer, late occurrence of menopause and extended exposure to ovulatory cycles at the end of menstrual life also increase risk. The breast cancer risk of women whose natural menopause occurs before age 45 is one-half that of women whose menopause occurs after age 55.29 Artificial menopause, induced either by bilateral oophorectomy or by pelvic irradiation, also markedly reduces breast cancer risk; this effect appears to be slightly greater than that of natural menopause.29

The relationship between weight and breast cancer risk is critically dependent on age. Among postmenopausal women, a 10-kg increment in body weight results in an approximately 80% increase in that woman’s risk of breast cancer.30 An explanation for this effect is that heavier postmenopausal women have higher circulating estrogen levels due to the conversion of the adrenal androgen androstenedione to estrone by enzymes present in body fat. In premenopausal women, the relationship between weight and risk is less clearly established, but if anything, the situation appears to be the reverse of that in postmenopausal women (i.e., high weight appears to be associated with reduced risk).31 This may result from the reduced frequency of ovulatory menstrual cycles associated with high body weight.

Assuming ovarian activity affects breast cancer risk, case-control studies of breast cancer should find higher levels of circulating estradiol among breast cancer patients than among healthy women.32 Bernstein and colleagues33 have described the results of two concurrent case-control studies in the United States (Los Angeles) and China (Shanghai). Overall, breast cancer patients had 14% higher serum estradiol concentrations, with a case-to-control excess of 17% in Chinese women and 11% in Caucasian American women, respectively. Los Angeles control women had 21% greater estradiol concentrations than Shanghai control women, and adjustment for body weight only accounted for 25% of this difference. A recent prospective study by Toniolo and colleagues34 found a significant increase in breast cancer risk, related to higher circulating levels of total and free estradiol. Similar results from several cohort studies have now been summarized by Thomas et al.35

As indicated above, a polymorphism in the CYP17 gene is associated with higher levels of circulating estrogen and progesterone.22 Interestingly, the high-risk allele (A2) is more common in Asian than American women. Age at menarche has decreased rapidly in most Asian populations; this is most likely due to improved nutrition, decreased frequency of childhood diseases, and a more sedentary lifestyle. In Los Angeles, Japanese women now have an age at menarche that is on average at least as early as their Caucasian counterparts,36 despite their lower average weight during late childhood and adolescence. The levels of circulatory estrogen are now highest in these Japanese women, and their breast cancer rates have risen to levels at least as high as those of Caucasian women.37 This remarkable change in breast cancer rates appears to be most readily explained by the consequence of full expression of their genetic phenotype, given a salutary childhood environment.

Age at First Birth

An early age at first birth (i.e., before age 20 years) protects against breast cancer, reducing a woman’s risk by about 50% relative to nulliparous women. Full-term pregnancies at later ages add smaller increments of protection.38 Women who have a very late first full-term pregnancy actually are at a higher risk of breast cancer than nulliparous women.38 This paradoxical effect of a late first full-term pregnancy has been repeatedly confirmed by epidemiologic studies. Furthermore, a recent full-term pregnancy increases risk. Among women giving birth during the previous 3 years, breast cancer risk is nearly three times higher than that of women of the same age, parity, and age at first birth whose most recent birth occurred at least 10 years earlier.39 Although some studies have found first trimester abortions, whether spontaneous or induced and occurring before the first full-term pregnancy,40–41 to be associated with a higher risk of breast cancer, this interpretation is contradicted by most recent studies.42,42a

On the basis of these results, it appears that a first pregnancy confers two contradictory effects on risk of breast cancer; a short-term increase in risk, followed in the long term by a substantial reduction in risk.38 This apparent paradox has a physiologic explanation based on patterns of estrogen as well as prolactin secretion and metabolism during pregnancy. During the first trimester, the level of bioavailable estradiol rapidly rises, an effect that is more apparent during the first than in subsequent pregnancies.43 Thus, in terms of estrogen exposure to the breast, the net effect during this early part of pregnancy is an increased risk that is equivalent to the exposure from several ovulatory cycles over a relatively short period of time. In the long run, however, this negative effect of early pregnancy on risk of breast cancer can be overridden by two beneficial hormonal consequences of completing the pregnancy. It has been reported that prolactin levels are substantially lower in parous compared with nulliparous women.44,45 Prolactin is a polypeptide hormone which regulates lactation and appears to enhance estrogen effects on breast tissue. In addition, parous women have been reported to have lower levels of bioavailable estradiol than their nulliparous counterparts.46 At a molecular level, it is likely that the hormonal changes during pregnancy induce irreversible differentiation and apoptosis in some cells, which had already accumulated one or more of the relevant somatic mutations necessary for breast cancer development.

Diet

Much attention has been focused on dietary differences, particularly fat consumption, to explain both the international pattern of breast cancer occurrence and changes in rates of breast cancer following migration to high-risk, usually Western nations from low-risk countries.47,48 International breast cancer mortality rates correlate highly with per capita consumption of fat in the diet (correlation coefficient, r = .93).48 When international breast cancer incidence rates rather than mortality rates are considered, the magnitude of the correlation coefficient is still very high (r = .84).48 As implied previously, nutrition likely influences breast cancer occurrence by modifying age at menarche and body weight, but the correlation of fat consumption with international breast cancer mortality remains highly significant, even after statistical adjustment for those factors.

Many case-control studies of fat consumption and breast cancer have found only small differences between cases and controls, generally no larger than the differences in total caloric consumption. However, Howe and colleagues49 recently combined 12 large case-control studies representing populations with a wide range of dietary habits and underlying rates of breast cancer to study the diet–breast cancer relationship. They found that the breast cancer risk of postmenopausal women was positively associated with both total fat uptake and saturated fat intake (approximately a 50% difference in risk between individuals in the highest versus the lowest quintile of intake). Nonetheless, cohort studies that have used food-frequency questionnaires to study the relationship with either total fat, saturated fat, or vegetable fat50–53 have found little or no difference in breast cancer risk over a wide range of fat uptake.54

High-fiber diets may protect against breast cancer, perhaps because fiber reduces the intestinal reabsorption of estrogens excreted via the biliary system.51 In one animal study, a high-fiber diet was associated with a reduced incidence of mammary cancer.55 Assessment of fiber intake in epidemiologic studies has been problematic because of a paucity of data on the fiber content of individual foods and disagreement about the most appropriate methods of biochemical analysis to determine the different types of fiber.

There have been several attempts to demonstrate a reduction in serum estrogen levels following dietary interventions that reduce fat or increase fiber intake.56 A recent meta-analysis of several studies demonstrated a 7.4% average reduction in estradiol levels of premenopausal women and a 23% reduction in postmenopausal women following trials of reduced dietary fat intake.56 This analysis could not distinguish between a direct dietary effect on hormone level versus an indirect effect through disruption of ovulatory cycles, in premenopausal women; however, whatever the mechanism, such a reduction in estradiol levels is potentially very important. The substantial effect of fat reduction on estrogen levels reported for postmenopausal women is largely dependent on the results of a single study.57

Exogenous Hormones

Hormone replacement therapy (HRT) and oral contraceptives (OCs) are the exogenous counterparts to endogenous hormonal exposures experienced by women and therefore are of concern as potential contributors to breast cancer risk.

Oral Contraceptives

The relationship of OC use to breast cancer risk has been the topic of many review articles.58 A recent combined analysis of 54 studies that included over 150,000 women has provided many important answers about the risk of breast cancer among users of combination OC (COC), i.e., OCs which provide an estrogen and progestin in combination in a single pill (Fig. 13.3). This analysis indicates that a modest increased risk of breast cancer is observed among current (relative risk, RR = 1.24) and recent (RR = 1.16) COC users. Age at first COC use modifies the association with recent use. For recent users, the risks are highest for those who began COC use before the age of 20 years. However, total duration of COC use was not associated with increased risk of breast cancer, once recency of use was taken into account. Although the scope of this combined analysis was broad, it still provides little information on COC effects 10 or more years after cessation of use. Moreover, most women who stopped use 10 or more years ago had used COCs for only short periods of time. Women who began use as teenagers are now becoming perimenopausal and postmenopausal. Current studies now underway will be able to examine more complex patterns of COC use, as related to breast cancer risk.

Figure 13.3. Relative risk of breast cancer by time since last use of combined oral contraceptives.

Figure 13.3

Relative risk of breast cancer by time since last use of combined oral contraceptives. Relative risk (given with 95% CI) relative to never-users, stratified by study, age at diagnosis, parity, age at first birth, and age at which risk of conception ceased. (more...)

Hormone Replacement Therapy

Hormone replacement therapy increases breast cancer risk. A recent combined analysis of 51 studies that included over 160,000 women showed that for current or recent HRT use, breast cancer risk increases with increasing duration of use59 (Fig. 13.4). For women who had used HRT within the past 5 years prior to diagnosis, risk increased by 2.3% (p = .0002) for each year of use. However, women who stopped HRT use 5 or more years before diagnosis had only a very modest, nonsignificant increase in risk, regardless of duration of use. The vast majority of data from this combined analysis pertained to estrogen-only replacement therapy (ERT). Combination hormone replacement therapy (CHRT), in which progestin is given sequentially or continuously with estrogen during a monthly cycle, has grown rapidly in popularity in the past two decades. Although the combined analysis suggested that risk of breast cancer associated with CHRT might be greater than for ERT, there were few long-term users of CHRT available for analysis so the risk estimates were statistically imprecise.59 Ross and colleagues have recently reported the largest study by far on the relationship of CHRT and breast cancer. They found that, for each 5 years of use, risk was almost four times greater for CHRT users than for ERT users.60

Figure 13.4. Relative risk of breast cancer by duration and time since last use of HRT according to extent of tumor spread relative to never-users, stratified by study, age at diagnosis, time since menopause, body mass index, parity, and the age of a woman when her first child was born.

Figure 13.4

Relative risk of breast cancer by duration and time since last use of HRT according to extent of tumor spread relative to never-users, stratified by study, age at diagnosis, time since menopause, body mass index, parity, and the age of a woman when her (more...)

Although this combined analysis was large and detailed, it may still fail to determine the true risk of breast cancer that can be attributed even to ERT since many differences exist between HRT users and nonusers. Users of HRT may have different opportunities for breast cancer diagnosis. For example, they may have more frequent mammographic and physician examinations. Women with a family history of breast cancer are more likely to be never-users, and HRT users are likely to be of higher social class and education. Laya et al.61 have provided direct evidence that current HRT use reduces the sensitivity and specificity of mammographic screening, most likely by increasing the radiographic density of the breast. Genetic determinants, like those that determine endogenous hormone levels, may also play a role in determining HRT use.62

Genetic Determinants

A family history of breast cancer is associated with an increased risk of the disease. This is particularly so if the history includes a woman who was affected at an early age or had bilateral disease. Whereas a two- to three-fold increase in the overall risk of the disease has been observed in first-degree relatives of women with breast cancer, a nine-fold increase in risk has been found in the first-degree relatives of premenopausal women with bilateral breast cancer. Very high risks (i.e., five-fold or higher increases) also have been found in women with multiple first-degree relatives with breast cancer.

The patterns of risk observed in epidemiologic studies among the relatives of women with breast cancer are consistent with the disease having a hereditary component. During the past 5 years, two genes (BRCA1 and BRCA2) have been cloned and sequenced from high-risk families.9,10 The initial estimates of penetrance of these genes were high. However, using more broadly selected families, the risk of breast cancer in women carrying a BRCA gene mutation appears to be less than 50%.63,64 More than 200 different mutations have been found in the BRCA genes. In BRCA1, two common mutations have been found in individuals of Ashkenazi Jewish descent: 185delAG occurs in about 0.9% and 5382insC in approximately 0.13% of Ashkenazi individuals.65–69 In BRCA2, the 6174delT mutation is found in about 1.5% of the Ashkenazi population, whereas the 999del5 mutation occurs in about 0.6% of the entire Icelandic population.65–69

Additional high-familial-risk genes are being sought. Germline p53 mutations (Li-Fraumeni syndrome), although very rare, suggest another potential mechanism of genetic susceptibility,11 as breast cancer is a common feature of this syndrome. The role of some of the more common allelic variations in estrogen metabolism genes (e.g., CYP17, CYP19, HSD17B1) in familial risk is also under investigation.4

Endometrial Cancer

Among the hormone-related cancers, etiologically the best understood is endometrial cancer. All the major demographic characteristics of the disease, as well as the major nondemographic risk factors, are explicable on the basis of cumulative exposure of the endometrium to that fraction of estrogen which is unopposed by the modifying influences of progesterone.2,3

Mitotic Activity in the Endometrium

Key and Pike have summarized the existing data on endometrial mitotic activity during normal menstrual cycles.70 Mitotic rates are low during days 1 to 4 of the cycle, then increase rapidly and remain stable thereafter until day 19, after which rates drop to essentially zero for the remainder of the cycle. There appears to be a lag period of about 4 days before the full stimulatory effects of unopposed estrogen, or the modifying influence of progesterone on endometrial mitotic activity, are fully apparent.

The cellular basis for the antiestrogenic activity of progestogens on the endometrium is well understood.2 Progestogens reduce the concentration of estradiol receptors and increase the activity of the 17ß-hydroxysteroid dehydrogenase type II enzyme (17BHSDII) that converts estradiol to estrone,71,72 a biologically less potent estrogen due to its lower affinity for cellular estrogen receptors. Luteal phase progesterone causes endometrial cells to differentiate to a secretory state and progestogen withdrawal leads to cyclic sloughing of endometrial tissue. There are several investigators pursuing the relationship between polymorphisms in the relevant candidate gene and susceptibility to endometrial cancer (see Table 13.2).

On the basis of the concept that frequency of mitotic activity is the primary determinant of endometrial cancer risk and that such activity is controlled by cumulative exposure to unopposed estrogens, one can readily predict the most important risk factors for this disease (Table 13.3). Pregnancies and OCs, which expose the endometrium to constant high levels of both estrogen and progestogen, should protect against endometrial cancer development. Estrogen replacement therapy and obesity should increase the risk. All of these predicted effects have been repeatedly well documented in epidemiologic studies.2,70

Table 13.3. A Summary of Established Hormonal Risk and Protective Factors for Endometrial Cancer.

Table 13.3

A Summary of Established Hormonal Risk and Protective Factors for Endometrial Cancer.

Estrogen Replacement Therapy

Hormone replacement therapy in the form of unopposed estrogen therapy gained widespread popularity in the United States during the 1960s and 1970s.73 Concomitant with this increasing usage, incidence rates of endometrial cancer in postmenopausal women also increased rapidly, especially on the West Coast, where use of ERT was particularly common.74 By 1975, the results of epidemiologic case-control studies, demonstrating a strong overall association between ERT and risk of endometrial cancer were being published.75,76 Literally dozens of studies have now documented a high relative increase in the risk of endometrial cancer following ERT.13 Risk is strongly related both to dose and duration of use, but high relative increments in risk follow even moderate doses taken for moderately long periods of time. Women who use ERT for 5 years or longer have approximately a 3.5-fold increase in risk compared with that of women who have never used such therapy (Fig. 13.5A).13

Figure 13.5. Age-specific incidence rates for cancers of the endometrium in women using estrogen replacement therapy (ERT) (A) and combination oral contraceptives (OCs) (B) for 5 years.

Figure 13.5

Age-specific incidence rates for cancers of the endometrium in women using estrogen replacement therapy (ERT) (A) and combination oral contraceptives (OCs) (B) for 5 years. Data are from the U.K. Birmingham Cancer Registry for the years 1968 to 1972. (more...)

While use of estrogen clearly increases the incidence of aggressive endometrial cancer, the overall mortality from endometrial cancer among affected users somewhat paradoxically is much lower than among nonusers who develop endometrial cancer.77 In fact, such women have little reduction in lifespan compared with healthy women of the same age. The reasons for this are not completely known, but this phenomenon likely can be explained largely by the increased medical surveillance among estrogen users. Women who use ERT tend to be closely monitored because the drug frequently induces vaginal bleeding. Part of the favorable survival experience also probably results from patients with estrogen-induced benign hyperplasia being misdiagnosed as endometrial cancer. While past users of ERT have a risk of endometrial cancer that is intermediate between that for current users of comparable duration and lifetime nonusers, risk in such women remains substantially elevated over baseline even after many years without treatment.78

As noted above, the newer regimens of HRT typically follow a pattern not unlike that of sequential OCs; an unopposed estrogen is given early in a monthly cycle, followed by estrogen combined with a progestogen for the last 10 to 12 days. This regimen attempts to reproduce the hormonal pattern of the normal menstrual cycle, albeit at lower levels of both estrogen and progestogen. One therefore might predict that this method of HRT might only partially offset the increased risk of endometrial cancer that is associated with unopposed ERT. If progestins are added for less than 10 days per month, the risk is only slightly reduced.79 However, regimens which include progestins for more than 10 days in a month, or are given continuously with estrogen do not increase risk of endometrial cancer above the baseline.79

Tamoxifen, an antiestrogen to the breast, acts as an estrogen agonist in the endometrium, and the risk of endometrial cancer is elevated by tamoxifen in a fashion analogous to that of ERT.80 The molecular basis of this agonist effect on the endometrium as opposed to the antagonist activity of tamoxifen on the breast, however, is not totally understood.

Body Weight

High body weight leads to increased risk of endometrial cancer at all ages.81–84 The three studies of postmenopausal women with the largest number of endometrial cancer cases and controls all show at least a doubling of risk between thin and heavy women.81–83,84 Adipose tissue is rich in an aromatase enzyme system that converts androstenedione to estrone. In turn, estrone can be converted directly to estradiol. In addition, protein binding of estrogens in blood is lower in obese women, so the amount of bioavailable estradiol in such women is higher than would be expected from the peripheral conversion of androstenedione to estrone alone.

The explanation for the substantially increased risk of endometrial cancer with obesity in premenopausal women is less obvious.82,84 Although obesity does appear to be associated with slightly increased levels of bioavailable estradiol in premenopausal women, this alone appears to be insufficient to account for such a profound effect. The more likely explanation is that obesity in premenopausal women is associated with amenorrhea and subnormal luteal-phase progesterone levels, thus resulting in prolonged exposure of the endometrium to unopposed estrogen.85

Oral Contraceptives

The role of estrogens as the principal cause of endometrial cancer is further supported by the markedly increased risk after a relatively short-duration use of sequential OCs, which deliver an unopposed estrogen during most of the monthly cycle.81 As potent as ERT and sequential OCs are in modifying the risk of endometrial cancer, these effects can be mitigated by the simultaneous administration of progestogens. A series of case-control studies have consistently demonstrated that COCs (the only type of OCs currently marketed), which deliver estrogen and progestogen simultaneously during each day of use, decrease the risk of endometrial cancer by 11.7% per year (Fig. 13.5B).13 Two prospective studies, the Walnut Creek Contraceptive Drug Study82 and the Royal College of General Practitioner’s Oral Contraceptive Study,83 have demonstrated similar decreases in risk. In most of these studies, risk of endometrial cancer steadily decreased with increasing duration of use.

Parity

The other major, established risk factor for endometrial cancer, low parity, also is readily explained by the unopposed estrogen hypothesis.85 The highest risk of endometrial cancer occurs in either married or unmarried nulliparous women, and an incremental decrease in risk occurs with each increment in parity. Nulliparous women have a risk of endometrial cancer that is three to five times that of women with parity of greater than three. This effect is expected as no endometrial mitotic activity occurs during pregnancy because of the persistently high progesterone levels.

Ovarian Cancer

The epidemiology of epithelial ovarian cancer, like breast and endometrial cancer, is well studied. However, the hormonal basis for ovarian cancer appears to differ from that of other hormone-induced cancers, in that one of the most important ovarian epithelial cell mitogens is a gonadotropin, follicle stimulating hormone (FSH) (see Table 13.2). The stimulus for cell division in ovarian cancer etiology is not only hormonal but also a secondary effect following ovulation.2 In this case, it has been proposed that the epithelial cells within the ovary or covering the ovarian surface are the cells of origin of ovarian cancer. These cells replicate during or after each ovulation; thus, any respite from ovulation would be protective against ovarian cancer. This hypothesis is supported by a large body of epidemiologic data, which consistently demonstrates that the risk of developing ovarian cancer decreases with increasing parity and with COC use (Table 13.4), both of which induce anovulation.

Table 13.4. A Summary of Established Hormonal Risk and Protective Factors for Ovarian Cancer.

Table 13.4

A Summary of Established Hormonal Risk and Protective Factors for Ovarian Cancer.

As with other hormone-related cancers, there is little evidence that any external carcinogen (e.g., tobacco, dietary fat) directly affects the risk of ovarian cancer. There is a small percentage of ovarian cancer linked to BRCA1;9 however, beyond these rare familial cases, the genetic basis of individual susceptibility to ovarian cancer is largely unstudied. As with breast and endometrial cancers, candidate genes include those involved in steroid biosynthesis (e.g., CYP17) and, importantly, the gonadotropin follicle stimulating hormone (FSH) gene (see Table 13.2). Estradiol and FSH have growth-stimulating effects on ovarian epithelial cells.86–88

As with breast and endometrial cancer, the age-incidence curve for ovarian cancer emphasizes the importance of ovulation in determining risk. The age-incidence curve of ovarian cancer can be brought into line with the familiar linear log-log plot of other non–hormone-dependent epithelial tumors, if ovarian age is considered as starting at menarche and proceeding at a reduced rate (roughly 30% of normal) during periods of anovulation, including the postmenopausal period.89

Parity

Parity has been consistently identified as a protective factor in these studies. Compared with parous women, nulliparous women have at least 50% greater risk of ovarian cancer.90,91 Each pregnancy confers additional protection, whether full-term or incomplete.92

Oral Contraceptives

Epidemiologic studies have consistently demonstrated that use of OCs decrease the risk of ovarian cancer, in a duration-dependent manner analogous for their protective effect on endometrial cancer risk.13,93–95 Casagrande and co-workers suggested that since the protection afforded by pregnancies and by OC use appeared to act through a common mechanism, periods of pregnancy and OC use could be combined into a single measure of “protected time.”96 They demonstrated that the risk of ovarian cancer clearly decreased as protected time increased. Other epidemiologic studies have confirmed this observation.97

Prostate Cancer

Prostate cancer is now the most frequently diagnosed cancer in American men, with an estimated 180,000 cases in 1999. It is also the second leading cause of cancer deaths in males, exceeded only by lung cancer, with an estimated 37,000 deaths from prostate cancer in 1999. The prostate is an androgen-regulated organ, and there is little disagreement that androgens are the major stimulus for cell division in prostatic epithelium.98 Thus androgens are strong candidates as major contributors to prostatic carcinogenesis. Nonetheless, there is still little direct evidence to date that androgens cause prostate cancer and insufficient indirect evidence to make a totally convincing case for a causal relationship, in part because there are no easily measurable hormonal events in men as exist in women (e.g., menarche, menopause, reproductive experiences) that can be related directly to an alteration in prostate cancer risk, and use of exogenous androgens in men is relatively uncommon.

The epidemiology of prostate cancer is dominated by three observations; (1) the profound international and racial-ethnic variation in incidence and mortality, historically reported to be as much as 80-fold between the extremes of high risk (African Americans) and low risk (native Japanese and Chinese) populations;99 (2) the occurrence of occult, subclinical prostate cancer at a relatively comparable prevalence, albeit much higher rate, among these same populations;100 and (3) the strong relationship between prostate cancer incidence and aging.5 Prostate cancer almost never occurs before age 50 years, but it is still the most common cancer of American men, in large part because the rate of increase in prostate cancer incidence with aging is greater than for any other cancer.

Some of the indirect evidence for a role of androgens in prostate cancer development has come from comparisons of hormonal patterns in healthy men from racial-ethnic groups at the extremes and in the middle of prostate cancer incidence. In fact, African American men have higher exposure to testosterone, the main biologically potent circulating androgen, than their Caucasian and Asian counterparts, beginning in the in utero period.101 African American women have testosterone levels that exceed those of Caucasian women by 50% or more in early pregnancy, an exposure that has been hypothesized to permanently alter the “gonadostat,” the hypothalamic-pituitary-testicular axis, in African American male offspring relative to Caucasians.102 African American men during young adulthood also have substantially higher circulating testosterone levels than their Caucasian counterparts (approximately 13 to 15% difference at age 20 years).103 Although this difference appears to dissipate with age, African American men still have slightly higher testosterone levels than Caucasians (≈3% higher) at age 40 years.104 Asian men, while showing no evidence of low circulating testosterone levels relative to Caucasians or African Americans at any age, have been shown to have substantially reduced levels of androstanediol glucuronide than either of these other two racial-ethnic groups.105,106 This hormone is an index of 5-alpha reductase activity, the prostatic enzyme which bioactivates testosterone to dihydrotestosterone, the most biologically potent human androgen.

Several other indirect lines of evidence point to a role of androgens in prostate cancer pathogenesis. Androgens are required for prostate cancer development or progression in most animal models of prostatic adenocarcinoma.107 Prostate cancer has never been reported to occur in eunuchs or men with constitutional 5-alpha reductase activity, groups with very low androgen activity and highly underdeveloped prostates.5 Prostate cancers, at least early in their course, are uniformly androgen dependent, and androgen ablation therapy has been the mainstay for treating early metastatic prostate cancer for many decades.99 More direct evidence for a role of androgens in prostate carcinogenesis comes from a well-designed prospective study, the Physicians Health Study, which demonstrated that healthy men in the highest quartile of circulating testosterone levels have 2.6 times the likelihood of subsequently developing prostate cancer compared with men in the lowest quartile.108

Genetic Basis for Androgen Involvement in Prostate Cancer Development

The relationship between genetic control of androgen biosynthesis and metabolic pathways and prostate cancer risk is just now beginning to be understood. Ross and colleagues recently published a description of a polygenic model of prostate cancer development related to genetic control of androgen pathways to the prostate, in which they also reviewed the current state of knowledge in this area.5 Although both genetic control of androgen biosynthesis outside the prostate and transport of androgens to the prostate are of interest, most research to date has centered around androgen activity within prostatic epithelial cells, especially with regard to (1) the androgen receptor (AR) gene encoding the androgen receptor, which is responsible both for androgen transport within prostate cells and for transactivation of genes with androgen response elements in their promoter region, and (2) the steroid 5-alpha reductase type II (SRD5A2) gene, which encodes the type 2 5-alpha reductase enzyme responsible for metabolic activation of testosterone to dihydrotestosterone in prostatic cells (see Table 13.1) (Fig. 13.6).

Figure 13.6. A diagram demonstrating the sites of activity of the gene products of the candidate genes in the polygenic model.

Figure 13.6

A diagram demonstrating the sites of activity of the gene products of the candidate genes in the polygenic model. Chol = cholesterol; DHT = dihydrotestosterone; HSD3ß1 = 3ß-hydroxysteroid dehydrogenase I; HSD3ß2 = 3ß-hydroxysteroid (more...)

The AR gene is located on the X chromosome and resembles other genes in the super family of nuclear receptor genes, in that it contains a DNA-binding domain, a ligand-binding domain, and a transcription modulatory domain encoded by exon 1.109 Within exon 1 is a highly polymorphic trinucleotide repeat (CAGn) sequence, which is of relevance to prostate cancer, in part because an expansion of this repeat is the cause of a rare X-linked adult-onset motor neuron disease, spinal and bulbar muscular atrophy or Kennedy’s disease.110,111 Men with this disorder show evidence of reduced androgenicity including low indices of virility and fertility as well as gynecomastia. This observation led to the hypothesis that differences in the length of the CAG repeat might be related to differences in androgen transactivation both within and outside the normal range of repeat lengths,112 that is, fewer repeats would be associated with increased transactivation compared with longer repeats. This hypothesis received support from in vitro transfection assays, in which there exists a negative linear relationship between transactivation using reporter genes and repeat length, both within the normal range and the abnormal range observed in men with Kennedy’s disease.113,114

This hypothesis further predicted that men with short CAG repeat sequences would have higher prostate cancer risk than men with longer repeats.112 Consistent with the hypothesis, African American men, at high risk of prostate cancer, have shorter CAG repeats on average than Caucasians, who in turn have shorter repeats on average than Asians, at low risk of prostate cancer.112 Three studies have now provided direct support for this hypothesis by showing that prostate cancer patients, especially those with advanced disease, have shorter CAG repeats on average than healthy control men.115–117 Recent evidence suggests that these differences in transactivation may be mediated by androgen receptor coactivators interacting differentially with different lengths of polyQ amino acid tracts encoded by the CAGs.118

There are two distinct 5-alpha reductase isozymes encoded by different genes. The type 2 enzyme, encoded by the SRD5A2 gene on chromosome 2p is the isozyme most active in the prostate.119 When the SRD5A2 was first cloned, only one polymorphism was described, a (TA)n dinucleotide repeat in the 3’ untranslated region (UTR).120 Even though unique alleles of this polymorphism were eventually described for both African Americans and Asians, no functional relevance was ever convincingly shown for this polymorphism nor was it consistently related to prostate cancer risk.121 Sequencing of SRD5A2 in men with high and low circulating levels of androstanediol glucuronide, the biochemical correlate of 5-alpha reductase activity, revealed seven missense substitution mutations.5 Genotypes of one of these, a valine to leucine substitution at codon 89 (V89) has been shown to be correlated with androstanediol glucuronide levels within and between racial-ethnic groups, but no relationship between these genotypes and prostate cancer risk has yet been reported.122 Recently, a second missense substitution mutation, an alanine to threonine substitution at codon 49 (A49T) was shown to be significantly related to prostate cancer risk, especially advanced disease, in both African Americans and Hispanics. Concurrently, it was reported that in vitro site-directed mutagenesis assays showed altered kinetic properties for the A49T mutation compared with the wild-type enzyme, with a substantial increase in the Vmax for conversion of testosterone to dihydrotestosterone at substrate (testosterone) levels above 0.5 μM.122

Adolescent and Young Adult Genital Cancer

Vaginal Adenocarcinoma

The work of Herbst and colleagues describing the association between in utero diethylstilbestrol (DES) exposure and vaginal adenocarcinoma provided the initial suggestion that estrogen might induce anomalous development in utero which would later have neoplastic consequences in the postpubertal period.123 These neoplasms developed within a limited age range (approximately ages 15 to 29 years); and the relevant exposure nearly always occurred during the first trimester of the index pregnancy. Vaginal adenocarcinomas appear to develop from Müllerian duct remnants that are induced by DES exposure to persist beyond early fetal life. These remain dormant during childhood and are activated at puberty.

Testis Cancer

The age-specific incidence rates of malignant germ cell tumors of the testis peak in early adult life, in a pattern that is similar to that of DES-induced vaginal adenocarcinoma.124 This correspondence suggests that the etiology of testicular germ cell neoplasms may also involve in utero hormonal exposure. Risk factors for testis cancer include a history of cryptorchidism, Caucasian race, and in utero exogenous estrogen exposure and may include maternal pregnancy-related nausea and obesity as well.

Men with cryptorchid testes have been reported to have relative risks of testis cancer ranging from 3 to 14, compared with men with normal testicular descent.125–127 A persistently undescended testis is often accompanied by other structural abnormalities. The testis is smaller, and tubule development and spermatogenesis are retarded. Sertoli cell development is delayed and Leydig cells are abnormal.128 It is not the abdominal location of the undescended testis that increases the risk of cancer in the undescended testis. After descent is achieved by surgical treatment, previously undescended testes retain a higher-than-normal risk of cancer.127,128 Furthermore, the contralateral, normally descended testis in patients with unilateral cryptorchidism is reported to have a two-fold increase in risk of cancer.126,128,129

Normal descent of the testis is under hormonal control. Animal experiments have shown that estrogen treatment of pregnant mice can lead to undescended and hypogenetic testes.130 Similar abnormalities have been reported in the male offspring of women exposed to DES and to OCs during pregnancy. Thus, it is likely that cryptorchidism is tied to estrogen levels early in pregnancy131 and represents another, sometimes intermediate, outcome of the pathway leading to germ cell testicular tumors.

Other potential risk factors for testis cancer may also be manifestations of excess free maternal estrogen during the critical gestation period. Excessive nausea during pregnancy of mothers of patients with testis cancer may be associated with an increased risk of testis cancer; the risk is greatest in those whose mothers’ nausea required medical treatment, and the risk is most noticeable in sons who were their mothers’ first live birth.125,126 Increased levels of bioavailable estradiol are found in the first trimester of pregnancy in women with hyperemesis gravidarum compared with controls and in the first trimester of a woman’s first compared with her second pregnancy.32,132 Since adipose tissue is a source of estrogen, the increasing risk of testis cancer observed with increased weight of the mother prior to the index pregnancy may also reflect an excess of bioavailable estrogen.133

Three of four studies of the relationship of exogenous sex steroid exposure in pregnancy and testis cancer have shown higher risk of testis cancer in sons who experienced in utero exposure to either DES, OCs, estrogen, or the estrogen-progestin combinations used in pregnancy tests, with reported relative risks ranging from 2.8 to 5.3.125,126,134,135

The rarity of testis cancer and, correspondingly, cryptorchidism, in African American males may represent a slight variation of this “estrogen excess” hypothesis.125 The substantially higher plasma testosterone as well as estrogen levels in African American women compared with Caucasian women early in gestation suggest the possibility that both hormones may be important factors in the development of the testis.41 The absolute excess of testosterone in the early gestation blood of African American women, by providing a “protected” environment for testicular development and descent, is one possible explanation for the subsequent lower incidence of testis cancer in African American male offspring. In rats, estrogen-inhibited testicular descent can be reversed by treatment with androgens.136

There is increased risk of testicular cancer for individuals with an affected first-degree relative, with reported increased risk ranging between 2 and 12. The risk appears to be higher in brothers of patients than in fathers of patients. Westergaard and colleagues found a two-fold increase in risk for fathers of testicular cancer patients.137 On the other hand, they found that brothers of patients were 12.3 times more likely to have testicular cancer (95% CI:3.3, 31.5). Swerdlow138 also reports increased risk for the twins of testicular cancer patients. Twins of patients were 37.5 times more likely to have testicular cancer than twins of nonpatients (95% CI: 12.3,115.6). The risk of cancer among brothers of patients compared with fathers of patients and for twins of patients suggests a role for both genetic and in utero factors to be important in testicular cancer.

A recent segregation analysis by Heimdal and colleagues139 using both Norwegian and Swedish families suggested that this cancer follows a recessive major gene model of inheritance. Under this model, the gene frequency was estimated to be 3.8%, suggesting that 7.6% of men would carry such a mutation, but that only homozygous carriers would be at increased risk for testicular cancer. Their segregation model suggests that the lifetime risk of testicular cancer for men who were homozygous for this recessive gene would be 43%. In 1995, Leahy and co-workers conducted a genome-wide search for a testicular cancer gene.140 Using a sib-pair multi-point analysis of 35 families, they found an area on chromosome 4 that suggests linkage under a recessive model of inheritance (LOD = 2.60), which supports the findings of the segregation analysis. Areas of chromosomes 5 and 18 also were suggestive of linkage to a recessive major testicular cancer gene using multi-point analysis (LOD = 1.50 and 1.91, respectively).

There are similarities in the epidemiology of ovarian and testicular germ cell tumors, even though the former are comparatively rare. The ovarian tumors tend to have a peak incidence rate in the young adult age range and, as for testis cancer, these rates have been increasing.141 Furthermore, the risk of these tumors is also associated with maternal exposure to hormonal drugs during the index pregnancy.142

Cervical Cancer

Numerous studies of the relationship between hormonal contraceptives and cervical neoplasia have been conducted; however, not much attention has been paid to the contribution of other hormonal factors to the etiology of this disease. A small study of cervical cell mitotic activity during the menstrual cycle has shown that the mitotic rate is almost double during the luteal phase of the cycle than in the follicular phase.143 The mitotic rate of postmenopausal women was only 33% of the rate of premenopausal women. These data would predict that the slope of the age-specific incidence curve for cervical cancer should decrease after menopause as it does for cancers of the breast, ovary, and endometrium. Mortality and incidence data that predate the widespread use of Pap screening suggest that this is true.144

The relationship between OCs and cervical cancer risk requires careful evaluation. Sexual factors such as age at first sexual intercourse and number of sexual partners, which are risk factors for cervical cancer, may also be associated with OC use. Furthermore, OC use is positively associated with the frequency of cervical Pap screening.145–147 This positive association would be expected to produce a positive association of cervical carcinoma in situ (CIS) with OC use, whether or not a true etiologic association exists. It would also be expected to downwardly bias any association of OC use with invasive cervical cancer, by detecting tumors at a premalignant or in situ stage. Few studies have adjusted for Pap screening history and sexual history in evaluating the relationship between OC use and cervical cancer risk. Recent case-control studies have examined the issue of a possible spurious association between OC use and cervical CIS but have not produced consistent results.148–150

Analytic studies involving OC use and invasive cervical cancer have focused almost entirely on squamous cell malignancies or have not provided analyses by cell type. Results for studies which included primarily squamous cell tumors provide some evidence that OC use increases the risk of invasive cervical cancer. For example, in a case-control study conducted by Brinton and associates,151 the relative risk for OC users was 1.5 times that of nonusers, after adjustment for possible confounding by sexual activity risk factors and for Pap screening history. In this study, long-term OC users (5 or more years) had an approximately two-fold higher risk than nonusers. Overall, women who had used OCs with a high estrogen content had the highest risk. Another case-control study found OC use to be a strong predictor of risk of invasive squamous cell cervical cancer, but only if use of OCs began before 18 years of age.152

An increasing incidence of adenocarcinoma of the cervix has been reported among women under 35 years of age in Los Angeles County, California153 and in areas served by population-based cancer registries participating in the Surveillance, Epidemiology, and End Results (SEER) Program.154 In these areas, incidence of the same tumor type has remained essentially constant over the same period among older women. Peters and co-workers153 hypothesized that the use of OCs during the teenage years might account for this trend, as OCs produce morphologic changes in the endocervix, characterized by stromal edema, excessive mucus production, and glandular hyperplasia.155 The extent of these histologic changes increases with longer continuous use of the contraceptive agents.156 A population-based case-control study conducted in Los Angeles that was limited to young women (born after 1935) who had been diagnosed with adenocarcinoma of the cervix was recently published.157 On the basis of personal interviews of 195 patients and 386 age-, race- and neighborhood-of-residence–matched controls, the risk of adenocarcinoma of the cervix was greater among women who had used OCs than among those who had not. The highest risk was observed with OC use that exceeded 12 years.

Thyroid Cancer

The pituitary hormone thyroid stimulating hormone (TSH) is the principal hormone regulating the growth and function of the thyroid gland and thus, excess TSH may be of etiologic importance in the development of thyroid cancer.158 This hypothesis is supported by the observation that growth of some thyroid cancers depends on TSH secretion, so that suppression of TSH release by administration of thyroxin is often an effective treatment for thyroid carcinomas.159 Experimental studies provide further support for this hypothesis. Sustained elevation of TSH induces thyroid tumors in rodents.160,161 The actual mechanism by which elevated TSH levels have been achieved in these studies appears unimportant as thyroid tumors have been produced by iodine-deficient diets, by blocking thyroid hormone synthesis, by administering TSH directly, and by chemical goitrogens.162

In the United States, thyroid cancer is roughly 2.5 times more common in women than in men. Incidence rates in women increase sharply from childhood to age 30 years and then level off, whereas in men, thyroid cancer incidence rates increase gradually over the lifespan. The ratio of female-to-male incidence rates is greatest between the ages of 20 and 35 years, during which women have 4 to 5 times the risk of men. This ratio remains above 3 until menopause when it begins to level off around 1.5. This pattern suggests that sex hormones may play an important role in the development of thyroid cancer. A number of epidemiologic studies have shown a strong association between select reproductive factors and thyroid cancer risk. A history of pregnancy has been associated with elevated risk of thyroid cancer in several case-control studies, and the risk was especially elevated among women with pregnancies terminated by spontaneous or induced abortions.163–167 Diffuse enlargement of the thyroid gland occurs during pregnancy as a compensatory response to the increased requirement for thyroid hormone production.168 This alteration in normal thyroid function occurs primarily during the first trimester and seems to level off by 20 weeks of gestation, suggesting that changes in thyroid cells may occur early in pregnancy.169 It is possible that some of these cellular changes during the first few weeks of pregnancy may alter thyroid cancer risk, and that these changes may be mitigated by full-term pregnancy, but persist following early termination of a pregnancy.

Osteosarcoma

The age-specific incidence curve for osteosarcoma shows a distinct peak during adolescence.2 Epidemiologic findings strongly suggest that the adolescent peak in incidence is associated with the pattern of childhood skeletal growth. Osteosarcomas in adolescents occur most frequently in the epiphyses of long bones, the sites of maximal bone growth, and often occur in conjunction with the adolescent growth spurt when skeletal growth is maximal.170,171 Skeletal growth results from a combination of factors, but hormonal activity is a primary stimulus.

During the preadolescent period, from about age 5 to age 11 years, girls grow faster than boys, but their growth stops earlier so that by the middle to late teenage years, males are considerably taller.172 The age-specific incidence curves for osteosarcoma follow the same pattern. Osteosarcoma rates for girls up to about age 13 years are roughly 30% higher than those for boys. In the 15- to 24-year-old age group, the male rate exceeds the female rate by some 140%. African Americans are known to have proportionately longer legs and arms than Caucasians despite similar adult heights. Their rates of osteosarcoma under age 25 years are higher than those of Caucasians, with all of the excess incidence resulting from long-bone tumors.173

Conclusion

As our understanding of the relationship between epidemiologic risk factors and the circulating levels of the relevant hormones grows, avenues for primary prevention are becoming apparent. The control of obesity has obvious implications for both endometrial cancer and postmenopausal breast cancer. More information on the relationship between childhood diet and physical activity and the onset of puberty, in conjunction with the hormonal physiology of adolescence and young adulthood may provide increasing avenues for preventing breast, ovarian, and endometrial cancer in women and perhaps even prostate cancer in men. A large hormonal chemoprevention trial for breast cancer using the antiestrogen drug tamoxifen has already proven successful and an additional national trial using an alternative selective estrogen receptor modulator (SERM), raloxifen, without the same estrogen agonist effects on the endometrium is underway. A national trial to prevent prostate cancer through use of finasteride, a 5-alpha reductase inhibitor, has completed the recruitment phase. Hormonal chemoprevention of ovarian and endometrial cancer is already occurring in the population as a whole through the widespread use of COCs, and of endometrial cancer with increasing use of CHRT. A growing knowledge of the mutations and polymorphisms in genes causing increased risk of these cancers should lead to better definition of individual susceptibility. It should then be possible to focus intervention strategies on the higher-risk subgroups of the population.

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