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Estrognes steroidal


CONTENTS

Cancer Studies in Humans .3 Cancer Studies in Experimental Animals .4 Studies on Mechanisms of Carcinogenesis.4 Properties. 4 Use . 5 Production . 6 Exposure . 6 OESTRADIOL-17b, OESTRADIOL 3-BENZOATE. 8 Experimental data . 8 Human data. 8 Evaluation. 8 Experimental data . 8 Human data. 9 Evaluation. 9 Experimental data . 9 Human data. 9 Evaluation. 9 Experimental data . 10 Human data. 10 Evaluation. 10 CHEMICAL IDENTIFICATION . 10 OTHER RELEVANT INFORMATIONS. 10
INTRODUCTION (RoC)
Steroidal estrogens are cholesterol derivatives comprising a group of structurally related,
hormonally active molecules that control sex and growth characteristics. The National Toxicology
Program previously evaluated some specific steroidal estrogens, including conjugated estrogens
(listed in the Fourth Annual Report on Carcinogens in 1985 as known to be human carcinogens)
and a number of individual nonconjugated steroidal estrogens, including estradiol-17β, estrone,
ethinylestradiol, and mestranol (which also were listed in the Fourth Annual Report on Carcinogens
in 1985 as reasonably anticipated to be human carcinogens). In identifying steroidal estrogens
as carcinogenic to humans, the International Agency for Research on Cancer noted that its
evaluation applied to the group of chemicals as a whole and not necessarily to all individual
chemicals within the group (IARC 1987).
This listing of steroidal estrogens supersedes the previous listings of steroidal estrogens and
conjugated estrogens in the Report on Carcinogens and applies to all chemicals of this steroid class.
The profile for steroidal estrogens includes information on carcinogenicity, properties, use,
production, exposure, and regulations for steroidal estrogens as a class, as well as some specific
information for individual estrogens.

FOOD OCCURRENCE
(Roc)

Estradiol equivalent concentrations in meat and milk were determined by a uterine estrogen
receptor assay (a competitive protein binding assay).
Meat, including chicken, pork, and beef, was shown to contain 57 ± 29.5 pg of estradiol equivalents
(range 38 to 88 pg, n = 144), and milk to contain 53 ± 6.8 pg of estradiol equivalents (range 35 to
65 pg, n = 81) (Collins and Musey 1985). Veterinary use of steroidal estrogens (for growth
promotion and therapeutic purposes) can increase tissue levels in food-producing animals above
those resulting from endogenous estrogen production.
LEGISLATION
http://ec.europa.eu/food/fs/sc/scv/out21_en.pdf
http://ec.europa.eu/dgs/health_consumer/library/press/press57_en.pdf
http://www.fve.org/veterinary/pdf/food/directive_2003_74.pdf
http://www.efsa.europa.eu/en/efsajournal/doc/510.pdf

Methods of sampling and analysis
(Roc)
Gas chromatography with flame ionization detection is used to identify steroidal estrogens,
their components, and impurities. Infrared and ultraviolet absorption spectrophotometry and thin-
layer chromatography are the most common methods used to identify ethinylestradiol, mestranol,
estradiol, estriol, estrone, and estropipate. Liquid chromatography and high-pressure liquid
chromatography usually are used to assay their purity. Thin-layer chromatography, liquid
chromatography, ultraviolet absorption spectrophotometry, and potentiometric titration are used to
determine purity and content of various steroidal estrogens in pharmaceutical preparations (IARC
1999).



CARCINOGENICITY
(Roc)


Steroidal estrogens are known to be human carcinogens based on sufficient evidence of
carcinogenicity in humans.
Cancer Studies in Humans
Human epidemiological studies have shown that the use of estrogen replacement therapy by
postmenopausal women is associated with a consistent increase in the risk of uterine endometrial
cancer and a less consistent increase in the risk of breast cancer. Some evidence suggests that oral
contraceptive use also may increase the risk of breast cancer.
IARC (1999) evaluated the carcinogenic effects of estrogen replacement therapy used to relieve
symptoms of menopause and reported that an increased risk of endometrial cancer was associated
with increasing duration of estrogen therapy, as well as a small increased risk of breast cancer.
Studies since the IARC review have supported these findings. Four studies (one cohort study and
three large case-control studies) reported increased risk of endometrial cancer with estrogen
replacement therapy (Cushing et al. 1998, Shapiro et al. 1998, Persson et al. 1999, Weiderpass et
al.
1999), and three of these studies reported strong positive associations between risk of
endometrial cancer and duration of estrogen use. Three cohort studies of women taking either
estrogen replacement therapy or hormone replacement therapy (estrogen and progestogen
combined) found an association with breast cancer (Gapstur et al. 1999, Persson et al. 1999,
Schairer et al. 2000). Two of four case-control studies found that estrogen-only replacement therapy
was associated with an increased risk of breast cancer (Heinrich et al. 1998, Magnusson et al.
1999), whereas a third study reported a slight reduction in breast-cancer risk among women
receiving estrogen replacement therapy (Brinton et al. 1998), and a fourth found no association of
breast-cancer risk with hormone replacement therapy (Titus-Ernstoff et al. 1998).
One study found that estrogen therapy was associated with ovarian cancer (Purdie et al. 1999).
IARC (1999) also evaluated cancer risks associated with the use of oral contraceptives. Most of
these studies involved estrogen progestogen combinations. In general, oral contraceptive use was
associated with a small increased risk of breast cancer. Three case control studies published after
the IARC evaluation did not find an increased risk of breast cancer with oral contraceptive use
(Brinton et al. 1998, Titus-Ernstoff et al. 1998, Rohan and Miller 1999). Other studies indicated
that oral contraceptive use might decrease the risk of ovarian and endometrial cancer (Salazar-
Martinez et al. 1999), confirming the results of studies reviewed by IARC.
Since steroidal estrogens were listed in the Tenth Report on Carcinogens, additional
epidemiological studies have been identified.
These studies reported an increased risk of endometrial cancer among women using estrogen-only
therapy, supporting the findings of earlier studies (Epstein et al. 2009), and less consistent findings
for breast cancer in case-control studies of estrogen-only menopausal therapy (Prentice et al. 2008a,
2009, Calle et al. 2009, Jick et al. 2009). In 2009, IARC concluded there was sufficient evidence of
the carcinogenicity of estrogen-only therapy in humans based on increased risks of endometrial
cancer and ovarian cancer and limited evidence based on increased risk of breast cancer (Grosse et
al.
2009). The findings for ovarian cancer were based on two meta-analyses (Greiser 2007,
Zhou 2008). Since then, another meta-analysis has estimated a significant overall increase in
ovarian cancer risk related to duration of use of estrogen-only therapy (Pearce et al. 2009).
Since estrogen-only oral contraceptives were phased out starting in the mid 1970s, most of the
studies of oral contraceptive use have involved estrogen-progestogen combinations. In subsequent
reviews, IARC concluded that there was sufficient evidence of the carcinogenicity of combination
oral contraceptives in humans based on increased risks of breast, cervical, and liver cancer (IARC
2007) and sufficient evidence for the carcinogenicity of combined estrogen- progestogen
menopausal therapy in humans based on increased risk of breast cancer (Grosse et al. 2009). The
results of studies published since the 2007 review were consistent with the conclusions of the IARC
review, finding increased risk of breast cancer associated with both oral contraceptive use
(Rosenberg et al. 2009) and estrogen-progestogen menopausal therapy (Prentice et al. 2008b, 2009,
Calle et al. 2009, Chlebowski et al. 2009, Jick et al. 2009, Lyytinen et al. 2009). In both reviews,
IARC also noted that a lower risk of endometrial cancer was associated with oral contraceptive use.
The 2009 IARC review concluded that the risk of endometrial cancer associated with menopausal
therapy decreased with increasing duration of progestogen use. In two large studies of endometrial
cancer, combination therapy reduced the increase in risk of endometrial cancer associated with
estrogen-only therapy in women with higher body mass index (McCullough et al. 2008, Epstein et
al.
2009). A reanalysis of cervical-cancer cases from over 20 studies found an increased risk among
current oral contraceptive users (Appleby et al. 2007), supporting the results of the IARC review.
The IARC reviews and a reanalysis of 45 epidemiological studies (Beral et al. 2008) found that oral
contraceptive use was associated with a decreased risk of ovarian cancer.
Cancer Studies in Experimental Animals
In rodents, steroidal estrogens caused benign and malignant tumors, as well as pre-cancerous
lesions, in a variety of organs, including the mammary gland and female reproductive tract (IARC
1999). The strength of evidence in experimental animals differed among various estrogenic
compounds. Estrogenic compounds generally caused endometrial, cervical, and mammary-gland
tumors in mice, mammary and pituitary-gland tumors in rats, and kidney tumors in hamsters.

Studies on Mechanisms of Carcinogenesis
Although there is no evidence of genotoxic effects in non mammalian test systems, some steroidal
estrogens can damage mammalian DNA and chromosomes (IARC 1999). The most frequently
reported effects included DNA adduct formation, cytogenetic alterations (e.g., chromosome and
chromatid breaks, micronucleus formation, and sister chromatid exchange), and aneuploidy. Most
of these effects were demonstrated in various tests using animal cells or cell-free systems.
Studies with cultured human cell lines showed evidence of aneuploidy, DNA strand breaks,
micronucleus formation, and sister chromatid exchange. No data were found on genetic effects of
steroidal estrogens in humans in vivo.
Among mammals, including humans, metabolism is essentially similar for three naturally occurring
unconjugated estrogens: estradiol, estrone, and estriol are metabolized via similar phase I pathways
(aromatic hydroxylation to catechol intermediates) and phase II pathways (glucuronidation,
sulfonation, and O-methylation). The distribution of metabolic products depends on the target
tissue, species, strain, sex, and experimental conditions (IARC 1999).
The evidence is strong that estrogen carcinogenesis is mediated through activation of the estrogen
receptor. In addition, there is evidence that other mechanisms may play a role in the carcinogenic
effects of estrogens in some tissues. For example, prolonged estrogen exposure causes cell
proliferation in estrogen-dependent target cells, affects cellular differentiation, and alters gene
expression. Although the molecular mechanisms responsible for estrogen carcinogenicity are not
understood, the evidence indicates that estrogen carcinogenesis is complex, involving proliferative
effects and possibly direct and indirect genotoxic effects. The relative importance of each
mechanism is likely a function of the specific estrogen and of the exposed tissue or cell type and its
metabolic state (Yager and Liehr 1996).
Properties
Steroidal estrogens comprise a group of structurally related hormone molecules derived from the
cholesterol molecule (IARC 1979a). Estrogens are found in males and females, and are the primary
sex hormones in females. Steroidal estrogens are fat-soluble (lipophilic) molecules that are essential
for the growth, differentiation, and function of tissues in humans and other vertebrate animals.
“Estrogen” is a collective term for the naturally occurring female hormones estradiol, estriol, and
estrone. In females, estrogen is important in the development of secondary sexual characteristics, in
the regulation of the menstrual cycle, and in pregnancy. In males, estrogen is important in the
maturation of sperm. Estrogen also plays an important role in normal bone development and
maintenance in both males and females.
In the brain, estrogen affects factors regulating procreation, including reproductive behavior, mood,
and production and release of gonadotropins from the pituitary.
Both naturally occurring estrogens (e.g., estrone and estradiol- 17β) and synthetic estrogens (e.g.,
mestranol and ethinylestradiol) are widely used medicinal drugs. Estradiol-17β occurs as an
odorless, white or creamy-white crystalline powder with a molecular weight of 272.4 and a melting
point of 173°C to 179°C (IARC 1979b, 1999).
Estrone is an odorless, white to creamy-white crystalline powder with a molecular weight of 270.4
and a melting point of 254.5°C to 256°C. Estriol exists as very small, monoclinic crystals with a
molecular weight of 288.4 and a melting point of 282°C.
Conjugated estrogens are a noncrystalline mixture containing naturally occurring forms of mixed
estrogens, principally sodium estrone sulfate and sodium equilin sulfate. Piperazine estrone sulfate
is a synthetic conjugated estrogen. Conjugated estrogens generally occur as odorless, buff-colored
powders that are soluble in water.
Nonconjugated estrogens (both naturally occurring and synthetic) are practically insoluble in water
but slightly soluble to soluble in organic solvents (e.g., ethanol, acetone, diethyl ether, and
chloroform).
Mestranol is a white crystalline powder with a molecular weight of 310.4 and a melting point of
150°C to 151°C. Ethinylestradiol occurs as an odorless, creamy or yellowish-white crystalline
powder with a molecular weight of 296.4 and a melting point of 182°C to 184°C for the more stable
form and 141°C to 146°C for the less stable form.
Use
Estradiol-17β is the predominant estrogen in non-pregnant women, and estriol is the primary
estrogen produced during pregnancy.
Estradiol-17β and its metabolite estrone are secreted by the ovaries in women with normal
menstrual cycles and by the placenta in pregnant women. They both are essential for growth and
normal maintenance of the lining of the uterus, for development of the accessory and secondary
female sex characteristics, and for pregnancy (Prosser 1973). Conjugated estrogens, estradiol, and
synthetic esters of estradiol, especially ethinylestradiol and estradiol valerate, are most commonly
used for estrogen-replacement therapy or in combination with a progestogen for hormone-
replacement therapy. Unopposed estrogens, as commonly prescribed in the 1960s and 1970s, were
shown to cause endometrial cancer; however, addition of a progestogen greatly diminished
that risk (Loose-Michael and Stancel 2001). These replacement therapies are used to treat
symptoms of menopause, including menopause surgically induced by removing the ovaries.
Estrogens are used to prevent the sweating episodes called “hot flashes” and the shrinking and
irritation that sometimes occur in the vulva, vagina, and urinary tract during menopause. Estrogens
can be used to prevent common postmenopausal conditions such as osteoporosis and ischemic heart
disease and have been shown to decrease the rate of colorectal cancer. They also have been used to
treat low estrogen levels (hypoestrogenism) in males and females caused by hypogonadism,
castration, or primary ovarian failure (IARC 1999, HSDB 2009).
Estrogens have been used in oral contraceptives since the early 1960s. Steroidal estrogens, most
commonly ethinylestradiol, are also used with various progestogens in combined oral contraceptive
formulations.
Currently, many of the oral contraceptives used in the United States contain either 30 or 35 µg of
ethinylestradiol, because this dose has contraceptive efficacy, is well tolerated, and has a low risk of
side effects (e.g., such adverse events as breakthrough bleeding) (Schwend and Lippman 1996).
Mestranol is available only in combination with progestogens and is used in typical estrogen
therapies, particularly in some oral contraceptive formulations. Combined oral contraceptives
typically are administered as a pill taken daily for 20 to 22 days, followed by a seven-day pill-free
interval during which withdrawal bleeding is expected to occur (IARC 1999, HSDB 2009).
Steroidal estrogens are used to relieve certain symptoms of breast cancer in some women and men
with metastatic disease and are used in the treatment of prostate cancer (androgen-dependent
carcinoma).
Steroidal estrogens, often in combination with progestogens or androgens, are also used to treat
amenorrhea, endometriosis, and postpartum breast engorgement. Some estrogens, such as
conjugated estrogens and estrone, have been used in cosmetic products (IARC 1979b). Estrogens
(such as estradiol-17β and ethinylestradiol) are also used in a variety of veterinary treatments.
Steroidal estrogens are also used in biochemical research (HSDB 2009).
Production
In the United States, commercial production of some steroidal estrogens was first reported in the
late 1930s through the 1960s (estradiol- 17β in 1939, estrone in 1941, ethinylestradiol in 1945, and
conjugated estrogens in 1968) (IARC 1979b). Steroidal estrogens are isolated from the urine of
pregnant horses or are synthesized. The available data suggest that the metabolism of estrogens in
horses is similar to that in humans (IARC 1999). The principal estrogen present in conjugated
estrogens is sodium estrone sulfate (between 52.5% and 61.5%). The estrogenic potency of
conjugated estrogens is expressed by the equivalent quantity of sodium estrone sulfate. Conjugated
estrogens also contain sodium equilin sulfate (between 22.5% and 30.5%) (IARC 1999).
Ethinylestradiol, mestranol, estradiol, estradiol benzoate, and estradiol valerate are produced or
formulated in the United States, but no production figures have been reported (IARC 1999). In the
early 1970s, annual U.S. sales were estimated to be less than 50 kg (110 lb) for ethinylestradiol, 100
kg (220 lb) for mestranol, 100 kg (220 lb) for estradiol-17β, and 2,000 kg (4,400 lb) for estrone
(IARC 1974).
In 1975, U.S. production of 13 estrogenic and progestogenic substances, including conjugated
estrogens, amounted to about 10,500 kg (23,100 lb) (IARC 1979b). No recent data on production
volumes were found. Numbers of U.S. suppliers of selected steroidal estrogens in 2010 were 18 for
estradiol-17β, 15 for estrone, 14 for ethinylestradiol, 13 for mestranol, 1 for sodium estrone sulfate,
3 for piperazine estrone sulfate, and 1 for sodium equilin sulfate. (ChemSources 2010). U.S.
imports of “estrogens of animal or vegetable origin” were 6,765 kg (14,914 lb) in 2000 and 5,689
kg (12,516 lb) in 2009. Other import categories included “estradiol cyclopentylpropionate (estradiol
cypionate); estradiol benzoate,” with imports of 1,406 kg (3,100 lb) in 2000 and 653 kg (1,437 lb)
in 2009, and “estrogens not derived from animal or vegetable materials,” with imports of 8,766 kg
(19,325 lb) in 2000 and 1,002 kg (2,204 lb) in 2002. U.S. exports of “estrogens and progestins”
were 128,152 kg (282,522 lb) in 2000 and 29,028 kg (63,861 lb) in 2009 (USITC 2010).
Exposure
Under normal conditions, the ovaries produce estrogens in response to pituitary hormones. Estradiol
is the main naturally occurring estrogen.
Estradiol is substantially more potent at the receptor level than its metabolites estrone and estriol. In
a woman with a normal menstrual cycle, the ovary releases 70 to 500 µg of estradiol per day,
depending on the phase of the cycle. This estradiol is converted mainly to estrone and also to small
amounts of estriol. After menopause, most estrogen naturally occurring in a woman’s body comes
from peripheral tissues that produce estrone from androstenedione, a hormone released by the
adrenal cortex. Estrone and its sulfate-conjugated form, estrone sulfate, are the most abundant
circulating estrogens in postmenopausal women (IARC 1999). Estrone is found in the urine of
pregnant women and mares, in bulls and stallions, in ovarian fluids of many animals, in human
placentas, and in palm-kernel oil. Conjugated estrogens are naturally occurring substances found in
the urine of pregnant mares (IARC 1979b). Over 360 plants have been identified that have estrogenic activity, and a few plants contain the principal estrogens found in mammals (estradiol and estrone) (Setchell 1985). Meat and milk also may contain estrogens (Collins and Musey 1985). Veterinary use of steroidal estrogens (to promote growth and treat illnesses) can increase estrogens in tissues of food-producing animals to above their normal levels. Conjugated estrogens used in combined oral contraceptives are available as tablets, and those used for postmenopausal estrogen therapy are available in tablets, transdermal patches and gels, vaginal inserts and creams, subcutaneous implants, and injectable formulations. In 2009, over 84 million prescriptions were filled for brand-name and generic products containing estrogens (either conjugated or esterified) as an active ingredient (DrugTopics 2009a). The retail value of estrogen-containing products sold in that year exceeded $2.6 billion (DrugTopics 2009b). Oral contraceptive use in the United States began in 1960, but before then, estrogen preparations were used to treat menstrual disorders. Oral contraceptive use increased rapidly into the mid 1970s, but declined in the late 1970s because of increased awareness that oral contraceptives increased the risk of heart disease. The percentage of women born in the United States between 1945 and 1949 who have ever used oral contraceptives is 85%, compared with 60% of women born a decade earlier and less than 30% of women born before 1930. Pills with lower doses of estrogen were developed in the 1970s and 1980s, and those containing more than 50 µg of estrogen were slowly eliminated. The first combined oral contraceptive pills contained more than three times the amount of estrogen and progestogen used in current formulations. The standard dose is 30 to 35 µg of estrogen, with lower doses available (IARC 1999). The use of postmenopausal estrogen therapy also became common in the United States in the 1960s. Between 1962 and 1967, the number of women using this therapy increased by 240%. By 1967, approximately 13% of the women in the United States 45 to 64 years old used this type of therapy. The number of prescriptions for estrogens, not counting those used for oral contraceptives, increased from 15 million in 1966 to over 25 million in 1976. Prescriptions had declined to 15 million by 1982 because of concerns about endometrial cancer but again increased rapidly to 40 million by 1992. Doses used in postmenopausal estrogen therapy vary with the indication and the method of administration. Typical daily doses for treatment of menopausal symptoms are 0.625 to 1.25 mg of conjugated equine estrogens or 0.5 to 4.0 mg of estradiol. Minimal daily doses used to prevent osteoporosis are 0.625 mg of conjugated equine estrogens (pills), 2 mg of estradiol (pills), or 0.05 mg of estradiol (skin patch). Transdermal implants may contain 50 to 100 mg of estradiol and last for six to nine months (IARC 1999). Estrone has also been used in hormonal skin preparations for cosmetic use at concentrations of less than 0.1%. Unspecified estrogen and estrogenic hormones, which are believed to consist primarily of estrone, have been used in hormonal skin preparations (less than 0.1% to 5%), moisturizing lotions (1% to 5%), wrinkle-smoothing creams, hair conditioners, hair straighteners, shampoos, and grooming-aid tonics (less than 0.1%) (IARC 1979b). Potential exposure to steroidal estrogens in the workplace may occur through inhalation or dermal contact during production, processing, or packaging. In a facility producing oral contraceptives, mestranol was found in various sectors of the work environment at air concentrations ranging from 0.06 to 8.61 µg/m3 and on samples wiped from surfaces at levels of 0.003 to 2.05 µg/cm2 (IARC 1979b). The National Occupational Hazard Survey (conducted from 1972 to 1974) estimated that in 1970, 2,770 workers potentially were exposed to specific steroidal estrogens (ethinylestradiol, estrone, estradiol-17β) (NIOSH 1976). The National Occupational Exposure Survey (conducted from 1981 to 1983) estimated that 9,083 workers potentially were exposed to estradiol-17β and 4,444 to estrone (NIOSH 1990).
OESTRADIOL-17b, OESTRADIOL 3-BENZOATE
Experimental data
Oestradiol-17b and its esters were tested in mice, rats, hamsters, guinea-pigs and monkeys by
subcutaneous injection or implantation and in mice by oral administration. Its subcutaneous
administration resulted in increased incidences of mammary, pituitary, uterine, cervical, vaginal and
lymphoid tumours and interstitial-cell tumours of the testis in mice. In rats, there was an increased
incidence of mammary and/or pituitary tumours.
In hamsters, a high incidence of malignant kidney tumours occurred in intact and castrated males
and in ovariectomized females, but not in intact females. In guinea-pigs, diffuse fibromyomatous
uterine and abdominal lesions were observed. Oral administration of oestradiol-17b in mice led to
an increased mammary tumour incidence. Subcutaneous injections in neonatal mice resulted in
precancerous and cancerous cervical and vaginal lesions in later life and an increased incidence of
mammary tumours.
Oestradiol-17b has teratogenic actions on the genital tract and possibly on other organs and impairs
fertility.

Human data
No case reports or epidemiological studies on oestradiol-17b alone were available to the Working
Group.
Evaluation
There is sufficient evidence for the carcinogenicity of oestradiol-17b in experimental animals. In the
absence of adequate data in humans, it is reasonable, for practical purposes, to regard oestradiol-17b
as if it presented a carcinogenic risk to humans. Studies in humans strongly suggest that the
administration of oestrogens is causally related to an increased incidence of endometrial carcinoma;
there is no evidence that oestradiol-17b is different from other oestrogens in this respect.
ETHINYLOESTRADIOL
Experimental data
Ethinyloestradiol was tested in mice, rats, dogs and monkeys by oral administration and in rats by
subcutaneous injection; in most studies it was administered in combination with progestins.
When administered alone to mice, it increased the incidence of pituitary tumours and malignant
mammary tumours in both males and females and produced malignant tumours of the uterus and its
cervix in females. In rats, it increased the incidence of benign liver-cell tumours in both males and
females and produced malignant liver-cell tumours in females.
When ethinyloestradiol was given in combination with certain progestins, excess incidences of
malignant tumours of the uterine fundus were observed in female mice and of benign and/or
malignant mammary tumours in male rats; in female rats, the combinations reduced but did not
prevent the incidence of malignant liver-cell tumours when compared with that produced by
ethinyloestradiol alone. In dogs, no tumours that could
be attributed to the treatment were found. The study in monkeys was still in progress at the time of
reporting: no tumours had been found after 5 years of observation.
Mammary fibroadenomas were produced in female rats following subcutaneous injection of a
combination of ethinyloestradiol with megestrol acetate.
Ethinyloestradiol is embryolethal for preimplantation embryos in some species.

Human data
No case reports or epidemiological studies on ethinyloestradiol alone were available to the Working
Group.
Evaluation
There is sufficient evidence for the carcinogenicity of ethinyloestradiol in experimental animals. In
the absence of adequate data in humans, it is reasonable, for practical purposes, to regard
ethinyloestradiol as if it presented a carcinogenic risk to humans. The use of oral contraceptives
containing ethinyloestradiol in combination with progestins has been related causally to an
increased incidence of benign liver adenomas and a decreased incidence of benign breast disease.
Studies also strongly suggest that the administration of oestrogens is causally related to an increased
incidence of endometrial carcinoma; there is no evidence that ethinyloestradiol is different from
other oestrogens in this respect.
MESTRANOL

Experimental data
Mestranol was tested in mice, rats, dogs and monkeys by oral administration; in most studies it was
administered in combination with progestins. When administered alone, it increased the incidences
of pituitary tumours in both sexes of one strain of mice and increased the incidence of malignant
mammary tumours in castrated males of two further strains and in males and females of another
strain. It also produced an increased incidence of malignant mammary tumours in female rats.
Studies in dogs and monkeys are still in progress. Although no tumours have been observed in
either species after 7 years, no conclusive evaluation can yet be made.
In experiments in which mestranol was administered to female mice in combination with
norethynodrel, pituitary tumours and vaginal and cervical squamous-cell carcinomas were
produced; in male mice, an increased incidence of mammary tumours was observed following
administration of mestranol in combination with norethynodrel or ethynodiol diacetate.
Combinations with norethynodrel or norethisterone resulted in an excess of benign liver-cell
tumours in male rats and increased the incidence of malignant mammary tumours in
rats of both sexes.
In dogs, administration of combinations with various synthetic progestins led to the formation of
mammary tumours. In monkeys given these combinations as well as combinations with
norethynodrel or ethynodiol diacetate, no mammary nodules were observed after 5 and 7 years of
experimentation, respectively. These experiments are still in progress.
It was also tested in combination with norethynodrel by subcutaneous administration in mice, rats
and hamsters; it produced an increased incidence of mammary tumours in female mice.
Mestranol is embryolethal for pre- and postimplantation embryos in some species.

Human data
No case reports or epidemiological studies on mestranol alone were available to the Working
Group.
Evaluation
There is sufficient evidence for the carcinogenicity of mestranol in experimental animals. In the
absence of adequate data in humans, it is reasonable, for practical purposes, to regard mestranol as
if it presented a carcinogenic risk to humans. The use of oral contraceptives containing mestranol in
combination with progestins has been related causally to an increased incidence of benign liver
adenomas and a decreased incidence of benign breast disease. Studies also strongly suggest that the
administration of oestrogens is causally related to an increased incidence of endometrial carcinoma;
there is no evidence that mestranol is different from other oestrogens in this respect.
OESTRONE

Experimental data
Oestrone was tested in mice by oral administration; in mice, rats and hamsters by subcutaneous
injection and implantation; and in mice by skin painting. Its administration resulted in an increased
incidence of mammary tumours in mice; in pituitary, adrenal and mammary tumours, as well as
bladder tumours in association with stones, in rats; and in renal tumours in both castrated and intact
male hamsters.
Oestrone benzoate increased the incidence of mammary tumours in mice following its subcutaneous
injection.
Oestrone is embryolethal for preimplantation embryos in some species.

Human data
No case reports or epidemiological studies on oestrone alone were available to the Working Group.
Evaluation
There is sufficient evidence for the carcinogenicity of oestrone in experimental animals. In the
absence of adequate data in humans, it is reasonable, for practical purposes, to regard oestrone as if
it presented a carcinogenic risk to humans. Studies in humans strongly suggest that the
administration of oestrogens is causally related to an increased incidence of endometrial carcinoma;
there is no evidence that oestrone is different from other oestrogens in this respect.
CHEMICAL IDENTIFICATION (Roc)
Estrogen is a steroid hormone occurring naturally in both females and males. Hormones are
signaling molecules secreted into the bloodstream by endocrine cells; a hormone acts on target
cells that possess receptors for that hormone. Steroid hormones are fat-soluble (lipophilic)
hormones with a tetracyclic base structure, and are essential for the growth, differentiation, and
function of many tissues in both humans and animals. “Estrogen” is a collective term for the
female hormones, the most powerful of which is estradiol. These hormones control female
secondary sexual characteristics and prepare and maintain the uterine lining. Estrogens affect the
growth, differentiation, and function of peripheral tissues of the reproductive system, including
the mammary gland, uterus, vagina, and ovary. Estrogens also play an important role in bone
maintenance and exert cardioprotective effects. In the brain, estrogens modulate physiological
parameters important for regulating procreation, including reproductive behavior, gonadotropin
production and release from the pituitary, and mood. Both naturally occurring and synthetic
estrogens are widely used medicinal drugs (IARC 1999). Although estrogen is best known for its
critical role in influencing female secondary sexual characteristics, reproductive cycle, fertility,
and maintenance of pregnancy, less well known are the important actions of estrogen in male
tissues, such as the prostate, testis, and epididymis. In addition to their well-known role in female
bone formation and maintenance, estrogens are essential for the normal development of bone
tissue in males. Modification of the hormonal environment can increase or decrease the
spontaneous occurrence or induction of tumors.

OTHER RELEVANT INFORMATIONS

http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055436.htm

Source: http://www.iprev.it/uploads/media/ESTROGNES_Steroidal.pdf

mg-registry.net

Statistics Concentration)M. S. (Applied Statistics)University of the Philippines at Diliman, 1985Department of BiostatisticsUniversity of Alabama at Birmingham, Oct 2008 – presentCenter for Cardiovascular BiologyUniversity of Alabama at Birmingham, November 2010 – presentCenter for AIDS ResearchUniversity of Alabama at Birmingham, May 2008 – presentDepartment of BiostatisticsUniversity

Doi:10.1016/j.amjmed.2005.02.022

The American Journal of Medicine (2005) 118, 612– 617 CLINICAL RESEARCH STUDY Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall Brian F. Gage, MD, MSc,a Elena Birman–Deych, MS,a Roger Kerzner, MD,b Martha J. Radford, MD,c David S. Nilasena, MD, MSPH, MS,d Michael W. Rich, MDb aDivision of General Medical Sciences, Washington University

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