Hormones and cancer in humans

Fundamental and Molecular Mechanisms of Mutagenesis

ELSEVIER

Mutation

Research 333 (1995) 59-67

Hormones and cancer in humans Timothy J.A. Key Imperial

Cancer Research Fund, Cancer Epidemiology

*

Unit. Gibson Building, RadclifSe Injirma~.

O.rford OX2 6HE. UK

Abstract Hormones play a major role in the aetiology of several of the commonest cancers worldwide, including cancers of the endometrium, breast and ovary in women and cancer of the prostate in men. It is likely that the main mechanisms by which hormones affect cancer risk are by controlling the rate of cell division, the differentiation of cells and the number of susceptible cells. Hormones have very marked effects on cell division in the endometrium; oestrogens stimulate mitosis whereas progestins oppose this effect. The risk for endometrial cancer increases with late menopause, oestrogen replacement therapy and obesity, and decreases with parity and oral contraceptive use; thus risk increases in proportion to the duration of exposure to oestrogens unopposed by progestins, probably because unopposed oestrogens stimulate endometrial cell division. The effects of hormones on breast epithelial cell division in non-pregnant women are much less clear-cut than their effects on the endometrium. but both oestrogens and progestins appear to stimulate mitosis. Breast cancer risk increases with early menarche. late menopause and oestrogen replacement therapy. probably due to increased exposure of the breasts to oestrogen and/or progesterone. Early first pregnancy and multiparity reduce the risk for breast cancer, probably due to the hormonally-induced differentiation of breast cells and the corresponding reduction in the number of susceptible cells. Hormones do not have marked direct effects on the epithelial cells covering the ovaries, but hormones stimulate ovulation which is followed by cell division during repair of the epithelium. Risk for ovarian cancer increases with late menopause and decreases with parity and oral contraceptive use, suggesting that the lifetime number of ovulations may be a determinant of risk. For all three of these cancers risk changes within a few years of changes in exposure to sex hormones and some of the changes in risk persist for many years, indicating that hormones can affect both early and late stages of carcinogenesis. Understanding of the role of sex hormones in the aetiology of prostate cancer and of some rarer cancers is less complete. Kewnrds:

Sex hormone; Oestrogen: Progestin: Endometrial cancer: Breast cancer; Ovarian cancel

1. Introduction

The aim of this paper is to summarize current epidemiological knowledge concerning the effects of hormones on the occurrence of human cancers and to

* Tel.:

0865 311933:

0027-5 IO7/95/$09.50 SD/

Fax:

0

0027.5107(95)00132-8

0865 310545.

discuss the mechanisms which may underlie these observations. Emphasis is given to the three common cancers related to sex hormones in women. For these cancers it is possible that the main effects of hormones are achieved through their control of cell division, cell differentiation and the number of susceptible cells (Albanes and Winick, 1988; Cohen and Ellwein, 1990; Preston-Martin et al., 1990; MacMahon. 1993; Moolgavkar, 1993).

1995 Elsevier Science B.V. All rights reserved

2. Endometrial

2.1. &fects

cancer

of hormones

OFI

the normal endometrium

Oestrogens increase the mitotic rate of endometrial cells. Progestins oppose this effect by decreasing the concentration of oestrogen receptors (Hsueh et al., 19751, causing differentiation of the endometrial cells to a secretory state (Novak and Woodruff. 1979) and increasing the activity of oestradiol dehydrogenase (Tseng and Gurpide, 1975). During natural menstrual cycles the endometrial cell division rate increases rapidly at the beginning of the follicular phase. reaching a plateau despite the continuing increase in oestradiol concentrations. and then falls quickly to a very low level following the increase in progesterone during the luteal phase (Key and Pike, 1988a). Endometrial cell division is suppressed by pregnancy and combined oral contraceptives and stimulated by oestrogen replacement therapy.

2.2. Endogenous

hormones and endometrial

cancer

The rate of increase of incidence of endometrial cancer with age is very rapid until about age 50 but slower thereafter. and early menopause is protective (Pike, 1987). Pregnancies are strongly protective (Weiss. 1984; Kvlle et al., 1988). High levels of endogenous oestrogens are associated with an increase in risk (Austin et al., 1991: Nyholm et al., 1993). Obesity increases the risk for endometrial cancer both in postmenopausal and premenopausal women (Henderson et al.. 1983; Swanson et al.. 1993).

2.3. Exogerlolls hormones and e?ldOmetriUl cancer Combined oral contraceptives are strongly protective against endometrial cancer (Schlesselman. 1989), whereas sequential oral contraceptives increase risk (IARC, 1987). Use of combined oral contraceptives for 1 year reduces the risk by about 20%, and use for 4 years reduces the risk by more than 50%. The protective effect appears within IO years of starting combined oral contraceptive use and lasts for more

than 20 years (Levi et al., 1993; Stanford et al.. 1993a). It is not clear whether the protective effect of oral contraceptives varies with their formulation: Rosenblatt et al. (1991) found a significantly lower risk for women taking higher progestin dose preparations, but no significant difference in the relative risks when women were grouped according to the oestrogen content of the preparations, whereas Voigt et al. (I 994) concluded that the progestin potency of oral contraceptives did not alter their protective effect if they had been used for at least 5 years. There is some evidence that depot medroxyprogesterone acetate and progestin-only contraceptives also reduce risk (Cancer and Steroid Hormone Study. 1987a; World Health Organization. 1993). Oestrogen replacement therapy increases the risk of endometrial cancer (IARC. 1979; IARC, 1987) and the risk increases with increasing strength of medication and duration of use (IARC, 1979). Typical risks reported relative to non-users are 2.9. 5.6 and 10.0 for durations of use of l-4. 5-9 and IO + years, respectively (Shapiro et al., 1985). and 2.7 and 3.8 for usual doses of 0.625 mg or less and 1.25 mg or more of conjugated equine oestrogens, respectively (Buring et al., 1986). The excess risk is evident within a few years of starting oestrogen replacement therapy and is still observed IO or more years after last use (Shapiro et al., 1985; Levi et al., 1993). Previous reports that the risk decreased rapidly when oestrogen replacement therapy use ceased may have been due to misclassification of oestrogen replacement therapy-induced endometrial hyperplasia as cancer (Horwitz and Feinstein, 1986). Oestrogen replacement therapy increases risk more in thin women than in obese women (Brinton et al.. 1993; Levi et al.. 1993). Several studies have recently reported data on the effect of combined oestrogen and progestin replacement therapy on endometrial cancer risk (Persson et al., 1989; Voigt et al., 1991: Brinton et al.. 1993: Jick et al.. 1993). These studies are all based on relatively small numbers of women with cancer who had used combined hormone replacement therapy. These studies all reported relative risks close to unity. showing that combined treatment does not produce the large increase in risk seen for oestrogen only treatment. but also that it does not have the strong protective effect of combined oral contraceptives.

T.J.A. Ke~/Mutation

2.4. Conclusions cancer

on

hormones

and

endometrial

It is clear that unopposed oestrogens increase the risk for endometrial cancer and that progestins are protective. These relationships underlie the observed relationships of oestrogen replacement therapy, parity and combined oral contraceptives on risk. The increased risk associated with obesity in postmenopausal women may be largely due to increased production and bioavailability of endogenous oestrogens. The increase in risk associated with obesity in premenopausal women may be largely due to reduced progesterone production (Key and Pike, 1988a), although increased bioavailability of oestradiol might also play a role. It has been suggested that the risk of endometrial cancer is proportional to the mitotic rate of the endometrial cells and that the role of progestins is to shorten exposure to unopposed oestrogens, so that risk will increase under all patterns of exposure to an oestrogen unopposed by a progestin (Key and Pike. 1988a). This is consistent with the absence of a clear protective effect for combined hormone replacement therapy (progestins for up to 2 weeks of each 4-week treatment cycle). in contrast to the strong protective effect of combined oral contraceptives (progestins throughout the period of oestrogen treatment).

3. Breast cancer 3.1. Effects cells

of hormones on normal breast epithelial

The major effects of hormones on the breast occur at puberty and during pregnancy and lactation. Oestrogen alone causes rapid growth in breast size (Laron et al., 19891, but full development of the glands probably requires ovulatory menstrual cycles and takes several years (Russo et al., 1990). Breast epithelial cells proliferate rapidly and differentiate during pregnancy, resulting in a reduction in the number of undifferentiated cells (Russo et al.. 1990; Russo et al., 1994). During lactation there is very little proliferation but secretory changes occur (Battersby and Anderson, 1988). Breast tissue involutes after the menopause.

61

Research 333 (IYY.5) 59-67

Breast epithelial cells divide throughout the menstrual cycle, although not as rapidly as during pregnancy, with a peak during the luteal phase (Potten et al., 1988; Anderson et al., 1989). Oestrogen receptor levels are high in the follicular phase and low in the luteal phase, as in the endometrium, but in contrast to the endometrium progesterone receptor levels are high throughout the menstrual cycle (Battersby et al., 1992: Sijderqvist et al., 1993). These results show that progesterone does not inhibit breast cell division (Pike et al., 1993). Breast cell division rates in biopsies from women using combined oral contraceptives are at least as high as those from women with natural cycles (Potten et al., 1988; Anderson et al., 1989). and oral contraceptives containing high doses of ethinyl oestradiol stimulate breast cell mitoses more than those with a lower dose (Anderson et al., 1989). 3.2. Endogenous

hormones

and breast cancer

Early menarche and late menopause increase risk (Kelsey et al., 1993). Full-term pregnancies cause a short-term increase in risk followed by long-term protection. Studies of serum oestrogen concentrations and breast cancer risk in premenopausal women have not produced consistent results (Key and Pike, 1988b), but recent studies have confirmed earlier reports of a positive association between endogenous oestrogens and breast cancer risk in postmenopausal women (Bernstein and Ross, 1993; Toniolo et al., 1993). Breast cancer risk is also increased by postmenopausal obesity (Kelsey and Gammon, 1990). 3.3. Exogenous cancer

aestrogens

and progestins

and breast

Overall, combined oral contraceptive use does not have a significant effect on breast cancer risk. but risk is moderately increased in women below age 35 and in current and recent users (UK National CaseControl Study Group, 1989; Thomas et al., 1992). There are no established differences in the effects of different combined oral contraceptive formulations (Thomas et al., 1992). There is little data on progestins administered alone. The UK National Case-Control Study Group (1989) reported a statistically significant protective

62

T.J.A. Key/

Mututiorr

effect with increasing duration of use of progestinonly contraceptives. In a cohort of women with benign breast disease, Plu-Bureau et al. (1994) reported a statistically significant protective effect for ever-use of l9-nortestosterone derivatives but a non significant increase in risk associated with other progestins. A study of the effects of progestins given alone as treatment for endometriosis, menstrual and infertility problems and impending miscarriage reported a significant increase in risk for breast cancer with increasing duration of use of the group of progestins including lynestrenol, allylestrenol and cyproterone acetate, but no relationships of risk with use of other progestins (van Leeuwen et al., 1993). Two epidemiological studies have provided reliable data on the relationship of depot medroxyprogesterone acetate with breast cancer risk. Neither study found an alteration in risk overall, but both studies found some elevation in risk for the occurrence of breast cancer before age 35 and for recent use of depot medroxyprogesterone acetate (World Health Organization. 1993). Administration of diethylstilboestrol in large doses during pregnancy increases the subsequent risk of breast cancer (IARC. 1987). Most studies did not show an increase in risk until many years after exposure, suggesting that diethylstilboestrol has an effect at an early stage of carcinogenesis. The published studies have, however, been too small to assess whether there is a moderate increase in risk sooner after exposure. Oestrogen replacement therapy causes a small increase in the risk of breast cancer. which increases with increasing duration of use. The size of the increase in risk after long-term use has varied substantially between studies but has been estimated in a meta-analysis as between 15% and 29% after IO years of use (Steinberg et al., 1994). There is less information concerning whether the addition of a progestin to oestrogen replacement therapy alters the effect on breast cancer risk. Several studies have been published over the past 6 years, but the total number of women studied who have used combined therapy is still quite small, especially for long-term use. Overall. these studies suggest that risk for breast cancer increases in association with long-term use of combined therapy, but there is insufficient data to show whether the size of

Kr.w~c~rd~33.3 ( 1995) 59-67

the increase in gen treatment 1992: Persson Stanford et al..

risk is different from that for oestroalone (Ewertz. 1988: Colditz et al., et al., 1992: Schairer et al.. 1993: 1993b; Risch and Howe, 1994).

3.4. Conclusiom cailcet

on oeLstrogem. progestins and breast

The effects of early menarche and late menopause show that breast cancer risk is increased by increased duration of exposure to ovarian hormones, but they do not help to distinguish the effects of oestrogens and progestins. The serological studies and the effects of obesity and oestrogen replacement therapy show that, at least in postmenopausal women, risk is increased by higher levels of exposure to oestrogens. This could be due to a mitogenic effect of oestrogens on normal breast cells. cancerous breast cells, or both. The effect of progestins is not yet clear, but the results of the numerous studies of combined oral contraceptives and the recent studies of combined hormone replacement therapy show that synthetic progestins do not oppose the effect of oestrogens and may possibly cause a further increase in risk. This is consistent with the knowledge that progestins do not inhibit normal breast cell division. While the duration and level of exposure to ovarian hormones probably affect breast cancer risk by stimulating breast cell mitosis, the protective effect of pregnancies is probably due to breast cell differentiation and the consequent reduction in the number of susceptible cells (Russo et al., 1994). Some of the international differences in rates might be due to differences in the number of potentially susceptible cells (MacMahon. 1993). The main hormonal risk factors for breast cancer affect risk within a few years but their effects last for decades and perhaps for a lifetime. Therefore it appears that sex hormones affect both early and late stages in breast carcinogenesis.

4. Epithelial ovarian cancer

The majority of ovarian cancers epithelial cells covering the ovary.

arise from the which are not

T.J.A. Key/Mutation

sensitive. However. gomarkedly hormone nadotrophins have a profound indirect effect on epithelial cells by stimulating ovulation, because this is followed by cell division during the repair of the ovarian epithelium. 4.2. Endogewus

hormones

and ouarian cancer

Some but not all studies have found that the risk for ovarian cancer is increased by early menarche and late menopause (Franceschi et al.. 199la). The shape of the age-incidence curve for ovarian cancer indicates that menopause is strongly protective (Pike. 1987). However, the most striking feature of the epidemiology of ovarian cancer is the strong protective effect of pregnancy (Negri et al., 199 1; Whittemore et al., 1992a). Whittemore et al. (1992a) reported relative risks of 0.60, 0.53, 0.48 and 0.29 for women with one, two, three and six or more children, respectively, in comparison with nulliparous women. Incomplete pregnancies ending in spontaneous or voluntary abortions have a weaker protective effect (Negri et al., 19921. Some of the difference in risk between nulliparous and parous women may be due to an increase in risk associated with infertility (Whittemore et al., 1992a). Lactation is associated with a decreased risk of epithelial ovarian cancer (Risch et al., 1983; Whittemore et al., 1992a; Rosenblatt et al.. 1993). The reduction in risk occurs after short-term lactation and there is no further reduction in risk associated with long-term lactation. Several studies have reported an inverse association of ovarian cancer risk with tubal ligation and hysterectomy without ovariectomy (Whittemore et al.. 1992a). 4.3. Exogenous

hormones

and oL*arian cancer

Combined oral contraceptives have a strong protective effect against epithelial ovarian cancer (IARC, 1987). Typical risk reductions associated with combined oral contraceptives have been a 40% reduction after 3 years of use and a 60-808 reduction after 7 or more years of use (Schlesselman, 1989). The reduction in risk lasts for at least 15 years after cessation of use (Cancer and Steroid Hormone Study, 1987b; Franceschi et al.. 1991 b; Rosenberg et al..

Rexarch

63

333 (1995) 59-67

1994). There is some evidence that the protective effect is greater for higher dose preparations, but this is not certain (Cancer and Steroid Hormone Study, 1987b; Rosenblatt et al.. 1992; Whittemore, 1993). In contrast with the effect of combined oral contraceptives, there is little evidence that the use of depot medroxyprogesterone acetate is associated with a reduction in the risk of ovarian cancer, although existing studies have low statistical power to detect such an effect (IARC, 1987; World Health Organization, 1993). Most studies have found that oestrogen replacement therapy in postmenopausal women does not alter the risk for ovarian cancer (Whittemore et al., 1992a). 4.4. Conclusiorls ovarian cancer

on hormorws

and

the

risk for

Fathalla (197 1) suggested that ovulation might increase the risk of ovarian cancer due to the trauma to the epithelium and the subsequent cell division during repair. The other main hypothesis is that high levels of gonadotrophins increase risk. Whittemore et al. (1992b) concluded that many of their findings were consistent with both the ovulation and the gonadotrophin hypotheses. The ovulation hypothesis was not consistent with the greater protective effect of pregnancy than oral contraceptives in young women, but this difference may have been partly due to errors in classification of oral contraceptive use. The gonatrophin hypothesis was not consistent with the absence of altered risk in association with oestrogen replacement therapy. The protective effect of menopause, which is associated with a large increase in gonadotrophin levels, is strong evidence against the gonadotrophin hypothesis and in favour of the ovulation hypothesis (Mohle et al., 1985). Depot medroxyprogesterone acetate suppresses ovulation but does not substantially suppress gonadotrophins. The absence of a protective effect for this drug would therefore be at variance with the ovulation hypothesis but perhaps compatible with the gonadotrophin hypothesis, but the data available is not sufficient to draw conclusions on this. The protective effect of tubal ligation might be due to the removal of visibly abnormal ovaries at

64

T.J.A. Key/ Mututiorz Rrsrurch 333 (IUUSl F-67

surgery (Beral, 19851, but it might also be due to the prevention of the upward flow of carcinogens or to an increased frequency of abnormal menstrual cycles following tubal ligation (Hankinson et al., 1993).

5. Other cancers Growth of the prostate gland is dependent on testosterone, which is converted to dihydrotestosterone within the organ. There have been several case reports of prostatic cancer developing after androgen therapy, but these findings are not conclusive (IARC. 1987). Diethylstilboestrol causes clear-cell adenocarcinoma of the vagina in women exposed to large doses in utero (IARC, 1987). The cancers occur after menarche and in early adulthood (Herbst et al., 1977; Horwitz et al., 1988). Since exposure occurred in utero, it is reasonable to conclude that diethylstilboestrol can affect the first stage of carcinogenesis. The human papillomavirus is the main cause of cervical cancer (Mufioz et al.. 1992), but this does not preclude additional hormonal effects. Progestins, for example, have been reported to enhance the transforming and transcriptional efficiencies of papillomaviruses (Crook et al., 19881. Combined oral contraceptives and depot medroxyprogesterone acetate have been associated with an increased risk of invasive cervical cancer (Beral et al., 1988; Brinton et al., 1990; Herrero et al., 1990). but this association may be largely due to confounding by exposure to human papillomavirus. Combined oral contraceptives, and probably androgens, increase the risk of hepatocellular carcinoma (IARC. 1987; WHO Collaborative Study of Neoplasia and Steroid Contraceptives, 1989; Trichopoulos, 1992). The mechanism for these relationships is not understood, but receptors for oestrogens and androgens have been identified in liver cells (Eisenfeld and Aten, 1987). Exposure to diethylstilboestrol in utero may increase the risk of testicular cancer (IARC. 19871. The mechanism is unknown, but Henderson et al. (1988) have suggested that exposure to high levels of oestrogen during the first trimester of pregnancy causes developmental arrest of the foetal germ cells, and that stimulation of these cells by gonadotrophins

after puberty produces germ cell cancers. A recent study of testicular cancer reported that risk was positively associated with early puberty and low amounts of exercise, and suggested that these variables might be associated with increased duration and level of exposure to gonadotrophins (United Kingdom Testicular Cancer Study Group, 1994).

References Albanes, D. and M. Winick (1988) Are cell number and cell proliferation risk factors for cancer’? J. Nat]. Cancer Inst., 80. 172-775. Anderson. T.J.. S. Battersby. R.J.B. King. K. McPherson and J.J. Going (1989) Oral contraceptive use influences resting breast proliferation. Hum. Pathol.. 20. 1139-l 144. Austin. H.. J.M. Austin, E.E. Partridge. K.D. Hatch and H.M. Shingleton (1991) Endometrial cancer, obesity and body fat distribution, Cancer Res., 5 I. 568-572. Battersby, S and T.J. Anderson (1988) Proliferative and secretory activity in the pregnant and lactating human breast. Virchows Archives A. Pathological Anatomy, 413, 189-196. Battersby. S.. B.J. Robertson, T.J. Anderson, R.J.B. King and K. McPherson (1992) Influence of menstrual cycle. parity and oral contraceptive use on steroid hormone receptors in normal breast. Br. J. Cancer, 65. 601-607. Beral. V. (1985) The epidemiology of ovarian cancer, in: C.N. Hudson (Ed.), Ovarian Cancer. Oxford University Press, Oxford. pp. 2 I-3 I, Beral, V.. P. Hannaford and C. Kay (1988) Oral contraceptive use and malignancies of the genital tract. Results from the Royal College of General Practitioners’ Oral Contraception Study, Lancet. ii, 133 I - 1335. Bernstein, L. and R.K. Ross (1993) Endogenous hormones and breast cancer risk. Epidemiol. Rev.. 15. 48-65. Brinton. L.A.. W.C. Reeves. M.M. Brenes. R. Herrero, R.C. de Britton. E. Gaitan, F. Tenorio, M. Garcia and W.E. Rawls (1990) Oral contraceptive use and risk of invasive cervical cancer. Int. J. Epidemiol.. 19. 3-l I. Brinton. L.A., R.N. Hoover and the Endometrial Cancer Collaborative Group (1993) Estrogen replacement therapy and endometrial cancer risk Unresolved issues. Obstet. Gynecol. 8 I, X-271. Buring. J.E.. C.J. Bain and R.L. Ehrmann (1986) Conjugated estrogen use and risk of endometrial cancer. Am. J. Epidemiol., 134. 434-441. Cancer and Steroid Hormone (CASH) Study of the Centers for Disease Control and the National Institute of Child Health and Human Development (1987aJ Combination oral contraceptive use and the risk of endometrial cancer, JAMA. 257. 796-800. Cancer and Steroid Hormone (CASH) Study of the Centers for Disease Control and the National Institute of Child Health and Human Development ( lY87bJ The reduction in risk of ovarian

T.J.A. Ke~/Muration cancer associated

with oral contraceptive use. N. Engl. J. Med.. 316. 650-655. Cohen, SM. and L.B. Ellwein (19901 Cell proliferation in carcinogenesis, Science, 249. 1007-101 I, Colditz, G.A.. M.J. Stampfer, W.C. Willett. D.J. Hunter, J.E. Manson. C.H. Hennekens, B.A. Rosner and F.E. Speizer (19921 Type of postmenopausal hormone use and risk of breast cancer: 12 year follow-up from the Nurses’ Health Study. Cancer Causes and Control, 3. 433-439. Crook. T., A. Storey, N. Almond, K. Osbom and L. Crawford (19881 Human papillomavirus type 16 cooperates with activated ras and fos oncogenes in the hormone-dependent transformation of primary mouse cells. Proc. Natl. Acad. Sci. USA, 85, 8820-8824. Eisenfeld. A.J and R.F. Aten (19871 Estrogen receptors and androgen receptors in the mammalian liver. J. Steroid Biochem., 27. 1109-I 118. Euertz, M. (19881 Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark, Int. J. Cancer, 42, 832-838. Fathalla, M.F. (19711 Incessant ovulation - a factor in ovarian neoplasia? Lancet, ii, 163. Franceschi, S.. C. La Vecchia, M. Booth. A. Tzonou, E. Negri. F. Parazzini. D. Trichopoulos and V. Beral (199 la) Pooled analysis of 3 European case-control studies of ovarian cancer: II. Age at menarche and at menopause, Int. J. Cancer. 49. 57-60. Franceschi. S.. F. Parazzini. E. Negri, M. Booth. C. La Vecchia, V. Beral. A. Tzonou and D. Trichopoulos (199lbl Pooled analysis of 3 European case-control studies of epithelial ovarian cancer: III. Oral contraceptive use, Int. J. Cancer, 49, 61-65. Hankinson, S.E.. D.J. Hunter, G.A. Colditz, W.C. Willett, M.J. Stampfer, B. Rosner, C.H. Hennekens and F.E. Speizer t 19931 Tubal ligation. hysterectomy and risk of ovarian cancer. JAMA, 270, 2813-2818. Henderson. B.E., J.T. Casagrande, M.C. Pike, T. Mack. I. Rosario and A. Duke (19831 The epidemiology of endometrial cancer in young women. Br. J. Cancer. 47, 749-756. Henderson. B.E.. R. Ross and L. Bernstein t 1988) Estrogens as a cause of human cancer: The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res.. 48, 246-253. Herbst. A.L., P. Cole, T. Colton, S.J. Robboy and R.E. Scully t 19771 Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix. Am. J. Obstet. Gynecol.. 128, 43-50. Herrero, R., L.A. Brinton, W.C. Reeves, M.M. Brenes, R.C. de Britton. F. Tenorio and E. Gaitan (19901 Injectable contraceptives and risk of invasive cervical cancer: Evidence of an association, Int. J. Cancer, 46. 5-7. Horwitz. RI and A.R. Feinstein (1986) Estrogens and endometrial cancer. Responses to arguments and current status of an epidemiologic controversy. Am. J. Med., 8 I, 503-507. Horwitz, RI.. CM. Viscoli, M. Merino, T.A. Brennan, J.T. Flannery and S.J. Robboy (1988) Clear celi adenocarcinoma of the vagina and cervix: incidence, undetected disease, and diethylstilbestrol. J. Clin. Epidemiol., 41, 5933597. Hsueh, A.J.W., E.J. Peck, Jr and J.H. Clark (1975) Progesterone

Research 333 fIYYSI 59-67

65

antagonism of the oestrogen receptor and oestrogen-induced uterine growth. Nature, 254, 337-339. IARC (19791 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 21. Sex Hormones (II), International Agency for Research on Cancer, Lyon. IARC (19871 IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42. International Agency for Research on Cancer. Lyon. Jick, S.S., A.M. Walker and H. Jick (19931 Estrogens, progesterone, and endometrial cancer, Epidemiology, 4, 20-24. Kelsey, J.L. and M.D. Gammon (19901 Epidemiology of breast cancer, Epidemiol. Rev.. 12, 228-240. Kelsey. J.L.. M.D. Gammon and E.M. John (1993) Reproductive factors and breast cancer, Epidemiol. Rev., 15, 36-47. Key, T.J.A. and M.C. Pike (1988al The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: Its central role in explaining and predicting endometrial cancer risk. Br. J. Cancer. 57. 205-212. Key, T.J.A. and M.C. Pike (1988bJ The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer, Eur. I. Cancer Clin. Oncol., 24. 29-43. K&e, G., I. Heuch and G. Ursin (19881 Reproductive factors and risk of cancer of the uterine corpus: A prospective study, Cancer Res. 48, 62 17-622 1. Laron, Z., R. Kauli and A. Pertzelan (19891 Clinical evidence on the role of oestrogens in the development of the breasts, Proceedings of the Royal Society of Edinburgh, 95B. 13-22. Levi, F., C. La Vecchia, C. Gulie, S. Franceschi and E. Negri (19931 Oestrogen replacement treatment and the risk of endometrial cancer: an assessment of the role of covariates, Eur. J. Cancer. 29A. 1445-1449. MacMahon. B. (19931 Reproduction and cancer of the breast, Cancer, 71, 3 185-3 188. Mohle. J., A. Whittemore, M. Pike and S. Darby (1985) Gonadotrophins and ovarian cancer risk. J. Nat]. Cancer Inst., 75. 178-179. Moolgavkar. S.H. (19931 Cell proliferation and carcinogenesis models: general principles with illustrations from the rodent liver system, Environmental Health Perspectives, 101 (suppl 51, 91-94. Muiioa. N., F.X. Bosch, S. de Sanjose. T. Tfur. I. Izaarzugaza, M. Gili. P Viladiu, C. Navarro. C. Martos, N. Ascunce. L.C. Gonzalez, J.M. Kaldor, E. Guerrero. A. Lorincz, M. Santamaria, P. Alsonso de Ruiz, N. Aristizabal and K. Shah (1992) The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain, Int. J. Cancer, 52, 743-749. Negri. E.. S. Franceschi. A. Tzonou, M. Booth, C. La Vecchia, F. Parazzini, V. Beral. P. Boyle and D. Trichopoulos (19911 Pooled analysis of 3 European case-control studies: I. Reproductive factors and risk of epithelial ovarian cancer. Int. J. Cancer, 49. 50-56. Negri, E., S. Franceschi. C. La Vecchia and F. Parazzini (19921 Incomplete pregnancies and ovarian cancer risk, Gynecol. Oncol., 47. 234-238.

66

T.J.A.

Kex/

Mutcttion

Novak, E.R. and J.D. Woodruff (1979) Novak’s gynecological and obstetric pathology with clinical and endocrine relations. Philadelphia. PA. W.B. Saunders. pp. 17 I - 184. Nyholm. H.C.J.. A.L. Nielsen. J. Lyndrup, A. Dreisler, C. Hagen and E. Haug (1993) Plasma oestrogens in postmenopausal women with endometrial cancer. Br. J. Obstet. Gynarcol., 100. I 115-l 119. Person. 1.. H.-O. Adami. L. Bergkviat. A. Lindgren, B. Pettersson. R. Hoover and C. Schairer (1989) Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. Br. Med. J., 298, 147-151. Person. I.. J. Yuen. L. Bergkvist. H.-O. Adami. R. Hoover and C. Schairer (1992) Combined oestrogen-progestogen replacement and breast cancer risk. Lancet. 330. 1044. Pike, M.C. (1987) Age-related factor& in cancers of the breast. ovary, and endometrium. J. Chron. Dih.. 40. 59%69s. Pike. M.C.. D.V. Spicer, L. Dahmoush and M.F. Press (1993) Estrogens, progestogens. normal breast cell proliferation. and breast cancer risk, Epidemiol. Rev., 15, 17-35. Plu-Bureau, G.. M.G. Li, R. Sitruk-Ware. J.C. Thalabard and P. Mauvais-Jarvis ( 1994) Progestogen use and decreased risk of breast cancer in a cohort study of premenopausl women with benign breast disease, Br. J. Cancer. 70. 270-277. Potten, C.S.. R.J. Watson, G.T. William\. S. Tickle. S.A. Roberts, M. Harris and A. Howell (1988) The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br. J. Cancer. 5X. 163-170. Preston-Martin. S., M.C. Pike. R.K. Ross. P.A. Jones and B.E. Henderson (1990) Increased cell division as a cause of human cancer, Cancer Res., 50. 7415-7421. Risch. H.A. and G. R. Howe ( 1994) Menopausal hormone usage and breast cancer in Saskatchewan: A record-linkage cohort study. Am. J. Epidemiol.. 139. 670-683. Risch, H.A.. N.S. W&a, J.L. Lyon, J.R. Daling and J.M. Liff (1983) Events of reproductive life and the incidence of epithelial ovarian cancer, Am. J. Epidemiol.. I 17. 128-139. Rosenberg, L.. J.R. Palmer. A.G. Zauber. M.E. Warshauer. J.L. Lewis. B.L. Strom. S. Harlap and S. Shapiro (1993) A casecontrol study of oral contraceptive use and invasive epithelial ovarian cancer. Am. J. Epidemiol.. 139. 654-661, Rosenblatt. K.A.. D.B. Thomaa and the WHO Collaborative Study of Neoplasia and Steroid Contraceptives (1991) Hormonal content of combined oral contraceptives in relation to the reduced risk of endometrial carcinoma, Int. J. Cancer, 49. 870-874. Rosenblatt, K.A., D.B. Thomas, E.A. Noonan and the WHO Collaborative Study of Neoplasia and Steroid Contraceptives (1993) High-dose and low-dose combined oral contraceptives: Protection against epithelial ovarian cancer and the length of the protective effect, Eur. J. Cancer. 28A. I872- 1876. Rosenblatt. K.A.. D.B. Thomaa and the WHO Collaborative Study of Neoplasia and Steroid Contraceptives (1993) Lactation and the risk of epitheliul ovarian cancer. Int. J. Epidemiol.. 22. !92-197. Russo. J.. B.A. Gusteraon. A.E. Rogers. I.H. Russo, S.R. Wellings and M.J. van Zwieten C1990) Comparative study of human and

Rrsr~trdz

333 f 1995)

5Y-67

rat mammary tumorigenesib. Laboratory Investigation, 62, 24-p278. Russo. J.. A.L. Romero and I.H. Russo (1994) Architectural pattern of the normal and cancerous breast under the influence of parity, Cancer Epidemiology, Biomarkers & Prevention. 3, 219-224. Schairer, C., L. Brinton, P. Keyl, C. Byrne and S. Sturgeon (1993) Risk of breast cancer after menopausal estrogen and estrogenprogestin replacement therapy. Am. J. Epidemiol., 138. 61 I, Schlesselman. J.J. (1989) Cancer of the breast and reproductive tmct in relation to use of oral contraceptivea. Contraception, 40. 1-38. Shapiro. S., J.P. Kelly. L. Rosenberg, D.W. Kaufman. S.P. Helmrich. N.B. Roaenshein. J.L. Lewis. Jr.. R.C. Knapp, P.D. Stolley and D. Schottenfeld (1985) Risk of localized and widespread endometrial cancer in relation to recent and dihcontinued ube of conjugated estrogens. New Engl. J. Med., 3 13, 969-972. Siiderqvist. G.. B. von Schoultz. E. Tani and L. Skoog (1993) Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle, Am. J. Obstet. Gynecol.. 168, 874-879. Stanford, J.L., L.A. Brinton, M.L. Berman. R. Mortel. L.B. Twiggs. R.J. Barrett, G.D. Wilbanks and R.N. Hoover (1993a) Oral contraceptives and endometrial cancer: Do other risk factors modify the association? Int. J. Cancer, 54. 243-248. Stanford. J.L.. N.S. Weiss. J.R. Daling. L. Voigt. M.A. Rossing and L. Habel (1993b) Combined hormone replacement therapy and breast cancer risk. Am. J. Epidemiol.. 138. 610-61 I. Steinberg, K.K.. S.J. Smith, S.B. Thacker and D.F. Stroup (lY94) Breast cancer risk and duration of estrogen use: The role of atudy design in meta-analysis. Epidemiol., 5, 415-421, Swanson. C.A.. N. Potischman. G.D. Wilbanks. L.B. Twiggs. R. Mortel, M.L. Berman. R.J. Barrett. R.N. Baumgartner and L.A. Brinton (1993) Relation of endometrial cancer risk to past and contemporary body size and body fat distribution. Cancer Epidemiol.. Biomarkers Prevent.. 2, 321-327. Thomas, D.B.. E.A. Noonan and the WHO Collaborative Study of Neoplasia and Steroid Contraceptivea C1992) Breast cancer and specific typea of combined oral contraceptives. Br. J. Cancer. 65. I OX- I 13. Toniolo. P.. M. Levitz. A. Jacquotte. K. Koenig. R. Shore and B. Pasternack ( 1993) Prospective atudy of endogenous estrogens and breast cancer. Am. J. Epidemiol. 138. 601. Trichopouloa D. ( 1992) Etiology of primary liver cancer and the role of steroidal hormones, Cancer Causes and Control, 3. 3-5. Taeng. I. and E. Gurpide (I 975) Induction of human endometrial estradiol dehydrogenase by progestins. Endocrinology, 97, 825-833. UK National Case-Control Study Group (1989) Oral contraceptive use and breast cancer risk in young women. Lancrt. i. 973-982. United Kingdom Testicular Cancer Study Group (1994) Aetiology of testicular cancer: association with congenital abnormalities, age at puberty, infertility and exercise. Br. Med. J., 308, 1393- 1399.

T.J.A. Key/Mutation van Leeuwen. F.E., L. Bliek. E. Slump and M.A. Rookua (1993) Use of exogenous progestogens in relation to the risk of breast cancer. Am. J. Epidemiol. 138. 61 I. Voigt, L.F.. N.S. Weiss, J. Chu, J.R. Daling, B. McKnight and G. van Belle (I 99 1) Progestagen supplementation of exogenous oestrogens and risk endometrial cancer. Lancet, 338. 374-277. Voigt, L.F.. Q. Deng and N.S. Weiss (1994) Recency, duration, and progestin content of oral contraceptives in relation to the incidence of endometrial cancer (Washington. USA). Cancer Causes and Control. 5, 327-233. Weiss, N.S. (1984) Epidemiology of endometrial cancer: A review of hormonal and non-hormonal risk factors. in: A.A. Forastiere (Ed.). Gynecologic Cancer. New York, Churchill Livingstone. pp. 199-214. Whittemore. A.S. (1993) Personal characteristics relating to risk of invasive epitheliai ovarian cancer in older women in the United States. Cancer. 71, 558-565.

Research 333 (1995) 59-67

67

Whittemore. A.S.. R. Harris, J. Itnyre and the Collaborative Ovarian Cancer Group (1992a) Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women, Am. J. Epidemiol., 136, 1184-1203. Whittemore, AS., R. Harris. J. Itnyre and the Collaborative Ovarian Cancer Group (1992b) Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Am. J. Epidemiol., 136, 1212-1220. WHO Collaborative Study of Neoplasia and Steroid Contraceptives (1989) Combined oral contraceptives and liver cancer. ht. J. Cancer, 43, 244-259. World Health Organization (1993) Depot-medroxyprogesterone acetate (DMPA) and cancer: Memorandum from a WHO meeting, Bull. World Health Organization, 7 1, 669-676.