by Catherine Schairer, Ph.D.*
substances produced in the body, have
regulatory effects on specific organs.
Estrogens and progesterone are two hormones
produced predominantly in the ovary of
the female. Estrogens control the development
of feminine body characteristics, and
both estrogens and progesterone regulate
the menstrual cycle and pregnancy. Androgens,
which are produced predominantly in the
male, determine masculine body characteristics.
These hormones, or synthetic chemicals
that have similar effects, are used as
drugs for a variety of purposes.
women take "replacement" estrogens to
relieve the hot flashes, vaginal dryness,
and itching that may develop at menopause
when ovarian function decreases. They
are also taken by older women to retard
bone loss. The most frequently prescribed
estrogen in the United States is Premarin,
a natural estrogen. Between 1962 and
1975, there was a four-fold increase
in the use of estrogens for menopausal
symptoms in the United States. This was
followed by a parallel increase in the
incidence of cancer of the endometrium,
the lining of the uterus (Thomas, 1988).
An explanation for the rise in incidence
came from several studies which showed
nine- to 14-fold increases in the risk
of endometrial cancer associated with
long-term use of menopausal estrogens.
Subsequent studies have confirmed these
earlier findings and suggest that risk
is greatest among current and recent
users. There is also a fairly rapid decline
in risk after cessation of use, although
a small increase in risk remains for
former users (Brinton, 1984).
studies have shown a slightly increased
risk of breast cancer in different subgroups
of women who have used estrogens for
a long period or at relatively high doses.
A number of other studies, however, have
found no increased risk associated with
duration or dose, making it difficult
to draw firm conclusions about the risk
of breast cancer associated with the
use of estrogen replacement therapy (Brinton
et al., 1993).
evidence suggests no overall association
between menopausal estrogen use and risk
of ovarian cancer (Brinton, 1984), although
further research is needed to determine
whether replacement estrogens increase
risk of specific types of ovarian tumors
(Thomas, 1988). Of two studies that have
examined the relationship between menopausal
estrogens and eye melanoma, one found
no association (Gallagher et al., 1985),
and the other found a two-fold increase
in risk associated with menopausal estrogen
use (Hartge et al., 1989). Several studies
suggest that menopausal estrogens protect
against large bowel cancer (Burch et
al., 1975; Furner et al., 1989), while
others do not (Weiss et al., 1981; Potter
et al., 1983; Davis et al., 1989).
the recognition in the early 1980s that
use of progesterone or its derivatives
(collectively called progestins) may
offset the increased risk of endometrial
cancer associated with estrogen use,
it has become increasingly common to
prescribe pro- gestins in conjunction
with estrogens during a portion of the
most frequently prescribed progestin
in the United States is Provera (medroxy-progesterone
acetate), a derivative of progesterone.
While the addition of progestins to estrogen
replacement therapy appears to have definite
beneficial effects on endometrial cancer
risk (Persson et al., 1989; Voigt et
al., 1991; Brinton et al., 1993; Jick,
et al., 1993), further epidemiologic
studies are needed to determine the optimal
regimen needed to counteract the adverse
effects of estrogens, particularly after
prolonged use. Data regarding the effect
of estrogen/progestin replacement therapy
on risk of breast cancer are limited
and inconsistent. Early studies reported
a protective effect of the estrogen/progestin
combination, but a recent study reported
an increased risk of breast cancer in
long-term users of estrogens and progestin
in combination (Kelsey and Gammon, 1990).
Further studies are needed to clarify
contrast to the natural estrogens most
commonly used in estrogen replacement
therapy, the estrogens used in oral contraceptives
are synthetic. The most effective and
widely used oral contraceptives are "combination" pills,
taken for 21 days, that contain a fixed
amount of estrogen and progestin. These "combination" oral
contraceptives actually reduce a woman's
risk of some cancers. Studies have uniformly
shown a risk reduction of 40 to 50 percent
for ovarian and endometrial cancers in
women who ever used combined pills. The
risk decreases with increasing duration
of use, and some protective effect appears
to persist for at least 10 to 20 years
after discontinuation of use (Stanford,
1993, Rosenberg, 1994). However, sequential
oral contraceptives, in which estrogen
alone is taken during the first 14 to
16 days of the monthly cycle followed
by an estrogen-progestin combination
during the last five or six days, have
been associated with increases in the
risk of endometrial cancer (Van Leeuwen
and Rookus, 1989).
relationship between oral contraceptive
use and risk of breast cancer remains
unresolved despite numerous studies.
Although many studies have found that
oral contraceptive use does not increase
risk of breast cancer in most women,
most, but not all, studies have reported
that long-term use at an early age increases
risk in women under the age of 45 years
(Kelsey and Gammon, 1990). Prolonged
use of oral contraceptives has also been
linked to an increased risk of cervical
cancer (Brinton, 1991), but some doubt
remains as to the causality of this association.
Substantial increases in the risk of
liver cancer have also been associated
with oral contraceptive use in developed
countries where this cancer is very rare
(Rosenberg, 1991). However, no such elevation
in risk has been detected in countries
where hepatitis B virus is endemic and
liver cancer rates are high (WHO, 1989).
Present evidence suggests that there
is no causal link between oral contraceptive
use and cutaneous melanoma, cancers of
the kidney, the colon, the gallbladder,
or tumors of the pituitary (Milne and
acetate (DMPA), a long-acting progestational
injectable contraceptive, has been approved
for contraceptive use in more than 90
countries, including the United States.
However, concern that DMPA might increase
the risk of breast cancer in women delayed
its approval in the United States until
1992. Although data are limited, there
appears to be no overall increase in
breast cancer risk among women who have
used this form of contraception. However,
a two-fold increase in the risk of breast
cancer in women who started using DMPA
in the previous five years has been reported,
suggesting that DMPA may accelerate the
growth of preexisting tumors (Skegg,
1995). Data on DMPA use and risk of other
cancers are also limited, but suggest
no association with cervical or ovarian
cancer (WHO, 1993), or liver cancer (WHO
1991), and a protective effect against
endometrial cancer (WHO, 1993).
(diethylstilbestrol), a synthetic chemical
with estrogenic properties, has also
been linked to risk of cancer. It was
used for the prevention of miscarriage
and late complications of pregnancy during
the late 1940s and 1950s. Following several
studies in the late 1950s that reported
no beneficial effect of DES, use of the
drug gradually tapered off (Vessey, 1989).
In 1971, prenatal DES exposure was linked
in young women to clear-cell adenocarcinoma
of the vagina, a rare form of cancer.
Subsequent studies have also linked prenatal
DES exposure to clear-cell adenocarcinoma
of the cervix. Results from a number
of studies suggest that a woman exposed
to DES in utero has about a one in 1,000
chance of developing a clear-cell adenocarcinoma
of the vagina or cervix by the age of
34 years (Vessey, 1989). There is little
evidence, however, that prenatal exposure
to DES increases risk of other types
of cervical or vaginal cancers (Thomas,
have shown that males exposed to DES
in utero have a greater frequency of
abnormalities of the reproductive tract
than those not exposed. One of these
abnormalities, failure of the testes
to descend into the scrotum, is known
to increase the risk of testicular cancer.
In several studies, a higher proportion
of males with testicular cancer were
also exposed to DES in utero compared
to study subjects without testicular
cancer (IARC, 1987).
of breast cancer in women who were themselves
treated with DES to prevent abortion
have yielded inconsistent results and
further studies are needed to determine
whether the possible association is causal
(Thomas, 1988). Data on development of
other types of cancer in women exposed
to DES during pregnancy are too limited
to draw firm conclusions (IARC, 1987).
androgens are used in the treatment of
renal conditions, various types of anemias,
endocrine disorders, and generalized
weakness. They are also used by athletes
and body builders to enhance development
of skeletal muscles. Individual cases
of liver cancer have been linked to the
use of these substances, but well-designed
studies are needed to confirm or refute
a causal relationship with oral contraceptives
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the Environmental Epidemiology Branch, Division of
Cancer Etiology, National Cancer Institute, Bethesda,
syndicated from National