Tobacco and Public Health - TCSC Indonesia

512
SMOKING AND OVARIAN CANCER
Casagrande et al. (1979) extended this concept by suggesting that anovulation, resulting
from oral contraceptive use, reduces the risk of ovarian cancer. Epithelial clefts and
inclusion cysts frequently form within the ovarian stroma as part of ovulatory repair.
Cells lining the clefts or inclusion cysts may undergo metaplasia to resemble serous,
mucinous, or endometrioid epithelium, as well as neoplastic transformation to
produce tumors of serous, mucinous, or endometrioid histologic varieties.
The incessant-ovulation hypothesis is supported by inferences from epidemiologic
studies of ovarian cancer (Risch et al. 1983; The Cancer and Steroid Hormone Study
1987; Whittemore et al. 1992; Schildkraut et al. 1997). Hormonal, reproductive,
and environmental factors, such as oral contraceptive use, pregnancy, and tobacco
smoking, may modify risk of ovarian cancer via an impact on ovulation. A dose–
response decrease in risk with increasing parity (Hankinson et al. 1995) and with
increasing duration of oral contraceptive use (Gross and Schlesselman 1994) is consistently
observed in most studies. Evidence also suggests that tobacco smoking may
impair ovulation in women, since smoking is observed to be associated with delayed
conception (Baird and Wilcox 1985) and with reduced ovulatory response to
gonadotropin stimulation (Van Voorhis et al. 1992). Furthermore, ovarian atresia, caused
by exposure to polycyclic aromatic hydrocarbons contained in cigarette smoke, has been
shown in other species (e.g. rodents) (Mattison and Thorgeirsson 1978). Cigarette
smoking also results in earlier age at natural menopause (Cooper et al. 1999; Hardy
et al. 2000). With cigarette smokers having fewer lifetime ovulations than nonsmokers,
the repeated ovulation model predicts a lower risk of ovarian cancer among smokers.
Although the incessant ovulation hypothesis is supported by the above evidence as
well as by animal studies showing the proliferative behavior of the ovarian epithelium
following ovulation (Godwin et al. 1992), it is unable to explain appreciable discrepancies
between the amount of anovulation and the magnitude of effect on risk for several
ovulation-related factors (Risch 1998). Tobacco smoking may therefore influence the
risk of ovarian cancer through additional biologic mechanisms, unrelated to ovulation,
for example involving hormonal factors.
Gonadotropin–estrogen theory
Stimulation of the ovary by steroid hormones may play a causative role in the
pathogenesis of ovarian cancer. Under the gonadotropin–estrogen (hormonal) theory,
the initial stage in the development of epithelial ovarian cancer, as in the incessantovulation
hypothesis, involves repeated proliferation and invagination of the ovarian
surface epithelium to form clefts and inclusion cysts within the ovarian stroma.
Subsequent events including differentiation, further proliferation, and eventual malignant
transformation are mediated through hormonal stimulation (Cramer and Welch 1983).
Specifically, increased pituitary gonadotropin [follicle-stimulating hormone (FSH) or
luteinizing hormone (LH)] action and the resulting excessive estrogen (or estrogen
precursor) stimulation of ovarian epithelial cells is responsible for the increased risk of