Tobacco and Public Health - TCSC Indonesia

CRYSTAL N. HOLICK AND HARVEY A. RISCH 513
ovarian cancer development. Factors that affect estrogen regulation would influence
gonadotropin stimulation and risk indirectly (Cramer and Welch 1983).
The gonadotropin–estrogen hypothesis predicts that higher concentrations of FSH
and LH, leading to greater ovarian estrogen synthesis, would increase the risk of developing
ovarian cancer. This observation is consistent with reports showing increased risk
associated with exogenous menopausal estrogen use (Hoover et al. 1977; Parazzini et al.
1994; Rodriguez et al. 1995; Purdie et al. 1996; Risch 1996; ). A number of common
chemicals or drugs are believed to enhance hepatic estrogen degradation or metabolism
(Helzlsouer et al. 1995). It is possible therefore that tobacco smoking may influence the
risk of epithelial ovarian cancer through hormonal mechanisms by altering the levels
of circulating estrogens. Women who smoke appear to have lower levels of urinary
estrogens, and other evidence of endogenous estrogen-deficiency (Wynder et al. 1969;
Van Voorhis et al. 1992). The reduced circulating estrogens in smokers could thus
result in a decreased risk of ovarian cancer.
There is very little direct evidence bearing on the gonadotropin–estrogen hypothesis.
The site distribution of ovarian epithelial tumors shows a larger fraction arising within
epithelial inclusion cysts, compared with the epithelial cells on the ovarian surface, and
the smallest fraction in the peritoneal mesothelium which has the greatest surface
area (Godwin et al. 1992; Resta et al. 1993). This suggests a hormonal influence on
neoplastic transformation. Studies evaluating the presence of ovarian epithelial cell
steroid–hormone receptors show at least low levels of estrogen receptors (al-Timimi
et al. 1985). Ovarian cancers mostly arise in the postmenopausal years, after the
large perimenopausal rise in gonadotropin levels. On the other hand, a nested
case–control study of prediagnostic serum gonadotropin and steroid hormone levels
showed that women with lower FSH levels were at increased risk of subsequently
developing ovarian cancer; there was no association with estrogen levels (Helzlsouer
et al. 1995).
Beyond estrogens: progesterone and androgens
The presence of progesterone and androgen receptors within ovarian epithelial cells
(al-Timimi et al. 1985; Zeimet et al. 1994) suggests that the epithelial cells are exposed
to and respond to both these hormones, and this has led to speculation on the involvement
of these hormones in the etiology of ovarian carcinogenesis (Risch 1998). It has
been suggested that the progestin exposure in oral contraceptive use (and in pregnancy,
for that matter) may be responsible for the protective effect, independent of or in addition
to anovulation (Risch 1998). One mechanism underlying the progestin hypothesis
may involve enhanced apoptosis of the ovarian epithelium (Rodriguez et al. 1998).
The degree of protection associated with oral-contraceptive use may be related to the
progestin potency of the formulation (Schildkraut et al. 2002).
Various epidemiologic and other studies support a role for androgens in the etiology
of ovarian cancer (reviewed in Risch 1998). In postmenopausal women, smoking