Progesterone Resource
Center
Hormones
by Catherine Schairer, Ph.D.*
Hormones, 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.
Many
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).
Numerous 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).
Most 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).
With 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 monthly cycle.
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 this issue.
In
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).
The 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 Vessey, 1991).
Depot-medroxyprogesterone 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).
DES (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, 1988).
Studies 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).
Studies 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).
Synthetic 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 (IARC, 1987).
REFERENCES:
Brinton LA: The relationship
of exogenous estrogens to cancer risk. Cancer Detect
Prevent 7:159-171, 1984.
Brinton LA: Estrogen replacement
therapy and endometrial cancer: Unresolved issues.
Obstet Gynecol 81:265-271, 1993.
Brinton LA and Schairer C: Estrogen
replacement therapy and breast cancer risk. Epidemiologic
Reviews 15:66-79, 1993.
Burch JC, Byrd BF and Vaughn
WK: The effects of long-term estrogen administration
to women following hysterectomy. Front Horm Res 3:208-214,
1975.
Davis FG, Furner SE, Persky
V, et al.: The influence of parity and exogenous
female hormones on the risk of colorectal cancer.
Int J Cancer 43:587-590, 1989.
Furner SE, Davis FG, Nelson
RL, et al.: A case-control study of large bowel cancer
and hormone exposure in women. Cancer Res 49:4936-4940,
1989.
Gallagher RP, Elwood JM, Rootman
J, et al.: Risk factors for ocular melanoma: Western
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1985.
Hartge P, Tucker MA, Shields
JA, et al.: Case-control study of female hormones
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on Cancer: Overall Evaluations of Carcinogenicity:
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Kelsey JL and Gammon MD: Epidemiology
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Milne R and Vessey M: The association
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1991.
Persson I, Adami HO, Bergkvist
L, et al.: The risk of endometrial cancer after treatment
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Potter JD and McMichael AJ:
Large bowel cancer in women in relation to reproductive
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Rosenberg L: The risk of liver
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Skegg DCG, Noonan EA, Paul C,
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Stanford JL, Brinton LA, Berman
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Thomas DB: Steroid hormones
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Van Leeuwen FE and Rookus MA:
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Vessey MP: Epidemiologic studies
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Weiss NS and Daling JR and Chow
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* From
the Environmental Epidemiology Branch, Division of
Cancer Etiology, National Cancer Institute, Bethesda,
Maryland
article
syndicated from National
Cancer Institute:
http<://seer.cancer.gov/publications/raterisk/risks83.html
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