Oestradiol valerate
The properties are the same oestradiol, so click to oestradiol for the details.
Oestradiol Dipropionate
Oestradiol Phenylpropionate
Oestradiol Valerate
A white crystalline powder which is odourless or has a faint
fatty odour. Practically insoluble in water; soluble in benzyl
benzoate, in dioxan. in methyl alcohol, and in castor oil: spar-
ingly soluble in arachis oil and sesame oil. Store in airtight
containers. Protect from light.
Adverse Effects
The adverse effects of oestradiol and other oestro-
gens are related, in part, to dose and duration of ther-
apy, and to the gender and age of the recipient. In
addition, adverse effects may be modified by con-
comitant administration of a progestogen in meno-
pausal hormone replacement therapy (HRT) or
combined oral contraceptives. Whether adverse ef-
fects of natural and synthetic oestrogens differ, and
the effect of route of administration, is less clear.
The use of oestrogens in girls may cause premature
closure of the epiphyses resulting in decreased final
adult height.
Large doses of oestrogens used in palliation of can-
cers have additionally been associated with nausea,
fluid retention, venous and arterial thrombosis, and
hepatic impairment. In men they cause impotence
and feminizing effects such as Gynaecomastia. In
women, they may cause withdrawal bleeding, and,
when used for breast cancer, they have caused hy-
percalcaemia and bone pain.
Effects on the skin. There is some evidence that transder-
mal patches in which oestradiol is dissolved in the adhesive
matrix cause fewer skin reactions than those employing re-
lease of oestradiol from an alcoholic reservoir.
Precautions
See estrogens for details.
High doses of oestrogen used in treating malignant
disease should be used cautiously in patients with
cerebrovascular disorders, coronary artery disease,
or venous thrombo-embolism. They may exacerbate
hypercalcaemia of malignancy.
Oestrogens should be used with caution in children
because premature closure of the epiphyses may oc-
cur resulting in inhibited linear growth and small
stature.
Oestrogens have been reported to increase the plas-
ma concentrations of cortisol- and thyroxine-bind-
ing globulin and hence may interfere with
diagnostic tests.
Cosmatic use. Some cosmetic products contain oestrogens
and their use has led to adverse effects such as precocious
puberty in children and gynaecomastia or postmenopausal
bleeding in adults.
Pregnancy. Although gross abnormalities of the genito-
urinary tract have been reported in the male offspring of
women who took stilboestrol during pregnancy there is con-
flicting evidence as to whether the oestrogen produced an
increased risk of abnormalities, infertility, or testicular
cancer in such offspring . The male fetus is normally
protected from the feminising effects of the natural oestro
gens in the uterine environment by the early development of
the testes and the secretion of male hormones.' However,
there has been considerable concern about a rising
incidence of disorders of the male reproductive tract, and
a reduction in sperm counts, which has been noted in the
last 20 to 30 years.
It has been hypothesised that overexposure of male fetuses
to environmental oestrogens derived from pollutants such as
pesticides and plastics may be responsible for this
decline, although some dispute this.
Veterinary use. An FAO/WHO expert committee consid-
ered it unnecessary to establish an acceptable daily intake or
acceptable residual level in food for endogenous hormones
such as oestradiol. Residues resulting from the use of oestra-
diol as a growth promoter in accordance with good animal
husbandry practice were thought unlikely to pose a hazard to
human health. However, it should be noted that in the Euro-
pean Union the use of steroidal hormones such as oestrogens
in veterinary practice is restricted, and their use as growth
promoters is banned.
There is concern about the effect of environmental oestrogens
on male fertility and development, see above.
Interactions
See estrogens
Pharmacokinetics
in general, oestradiol and other oestrogens are read-
ily absorbed from the gastro-intestinal tract and
through the skin or mucous membranes. However,
the natural unconjugated oestrogens such as oestra-
diol undergo extensive first-pass metabolism in the
gastro-intestinal tract and liver following oral ad-
ministration. They are, therefore, generally not oral-
ly active, although a micronised preparation of
oestradiol has sufficient bioavailability (3 to 5%) to
be orally active. Oestradiol is metabolised in part to
less active oestrogens such as oestriol and oestrone.
Synthetic oestrogens produced by alkylation of the
C;17 position, such as ethinyloestradiol. are more
slowly metabolised and are therefore orally active.
Conjugated oestrogens, which are essentially oes-
trogen metabolites, are also orally active because
they are hydrolysed by enzymes in the lower gastro-
intestinal tract allowing absorption of the active oes-
trogen. Vaginal, transdermal, or parenteral adminis-
tration of oestrogens also avoids first-pass hepatic
metabolism. Plasma-oestradiol concentrations are
reported to reach a peak 1.5 to 2 hours after oral ad-
ministration, and again at about 8 hours due to enter-
ohepatic recycling. Oestradiol esters are rapidly
hydrolysed to free oestradiol when administered by
mouth. Following intramuscular administration of
the esters, absorption is prolonged.
Oestrogens are extensively bound to plasma pro-
teins. Naturally occurring oestrogens such as oestra-
diol are principally bound to sex-hormone binding
globulin. Conversely, ethinyloestradiol is mostly
bound to albumin.
Oestrogens are metabolised in the liver. A variety of
sulphate and glucuronide conjugates are formed,
and these are excreted in the urine and the bile.
Those excreted in the bile undergo enterohepatic re-
cycling or are excreted in the faeces.
Uses and Administration
Oestradiol is the most active of the naturally occur-
ring estrogens .
Oestradiol and its semisynthetic esters and other
natural oestrogens are primarily used as menopausal
hormone replacement therapy (HRT),
whereas synthetic derivatives such as ethinyloestra-
diol and mestranol have a major role as components
of combined oral contraceptives . Oestradiol may also be
used as replacement therapy for female hypogonad-
ism or primary ovarian failure . Re-
placement therapy ('add-back' therapy) may also be
given to women in whom the pituitary-ovarian axis
is suppressed by therapy with gonadorelin or its an-
alogues.
For HRT orally administered preparations of oestra-
diol are commonly used, as are transdermal patches.
Transdermal gels and subcutaneous implants are
also available. Intramuscular injections were also
formerly used. In women with a uterus, associated
administration of a progestogen is required, given
cyclically or continuously and usually administered
by mouth although some transdermal preparations
are available. Local vaginal oestradiol preparations
are used specifically for the treatment of menopau-
sal atrophic vaginitis; these are generally recom-
mended for short-term use only, if given without a
progestogen in women with a uterus, although spe-
cific recommendations vary between products.
For administration by mouth oestradiol or oestradiol
valerate are normally employed: doses of I to 2 mg
daily are given cyclically or more often continuous-
ly.
β’ Oestradiol may be used topically as transdermal
skin patches to provide a systemic effect; a variety
of patches are available which release between 25
and 100 ng of oestradiol every 24 hours. Depending
on the preparation, patches are replaced once or
twice weekly. Each new patch is applied to a differ-
ent area of skin in rotation, usually below the waist-
line; patches should not be applied on or near the
breasts. Topical gel preparations are also applied for
systemic effect: the usual dose 1S 0.5 to 1.5 mg of
otstradiol daily. The gel should not be applied on or
near the breasts or on the vulval region.
In order to prolong the duration of action subcutane-
ous implants of oestradiol may be employed. The
dose of oestradiol is generally 25 to 100 mg with a
new implant being administered after about 4 to 8
months according to oestrogen concentrations.
Oestradiol may be applied locally either as 25-ng
vaginal tablets, at an initial dose of one tablet daily
for 2 weeks followed by a maintenance dose of two
tablets weekly, or as a 0.01% vaginal cream, in ini-
tial amounts of up to 4 g of cream daily followed by
a maintenance dose of I to 3 g weekly. Another lo-
cal delivery system employs a 3-month vaginal ring
containing 2 mg of oestradiol hemihydrate. which
delivers about 7.5 mcg of oestradiol per 24 hours.
Intramuscular injections of oestradiol benzoate or
valerate esters have been used as oily solutions to
provide a depot, usually administered once every 3
to 4 weeks. The cypionate, dipropionate. enanthate,
hexahydrobenzoate, phenylpropionate, and unde-
canoate esters have been used similarly.
Oestradiol and other oestrogens have sometimes
been used in-higher doses for palliative treatment in
prostate cancer and breast cancer in men and
postmenopausal women .
Administration. IMPLANTS. There may be a striking interpa-
tient variation in blood-oestradiol concentrations in women
receiving oestradiol implants. In addition. Gangar et al.z
noted that symptoms of oestrogen deficiency re-appeared in
some patients even though serum-oestradiol concentrations
were within or above the physiological range. This has led to
debate on the appropriateness of using serum concentrations
of oestradiol as a guide to implant administration, rather than
symptoms.3-7 Some felt that withholding an implant while a
patient suffered symptoms of oestrogen deficiency was
unacceptable34 and that other oestrogens or routes of admin-
istration may be more suitable. Although Gangar et al.'
thought that high oestradiol concentrations were probably not
harmful, others have pointed out that there was evidence to
the contrary, lending weight to the suggestion that oestradiol
concentration should be monitored during therapy with im-
plants and this is now recommended by the manufacturers.
Cyclical progestogen may be required for a prolonged period
after discontinuation of oestradiol implants in women with a
uterus.
TRANSDERMAL ADMINISTRATION. The Transdermal administra-
tion of oestradiol via patches applied to the skin has been re-
viewed. This method of delivery has certain advantages
over oral administration in that gastro-intestinal and hepatic
first-pass metabolism is avoided, liver enzymes are not stim-
ulated (although this may also mean that beneficial effects on
serum lipids are absent), and the prolonged drug release from
the patch means less frequent application is necessary and
hence patient compliance may be improved. For oestrogen re
placement in menopausal and postmenopausal women oestra
diol patches are administered continuously or in a cyclica
manner, with added progestogen for part of the cycle in those
women with an intact uterus. This does not lead to drug accu
mulation and produces blood-oestradiol concentrations an(
oestradiol to oestrone ratios similar to those normally ob
served in premenopausal women. Administration of oestradi
ol via a skin patch is well tolerated with skin irritation being
the main problem. The patches are as effective as orally ad-
ministered oestrogens in treating menopausal and postmeno-
pausal symptoms such as flushing and vaginal atrophy and
also appear to be as effective in preventing osteoporosis. but
further study is needed to determine whether this holds true
for reductions in cardiovascular disease risk.
Gender reassignment. Oestrogens such as ethinyloestra-
diol and conjugated oestrogens are used in male-to-female
transsexuals to develop and maintain secondary sexual char-
acteristics. There is some evidence this use improves vascular
function.
Growth disorders. A discussion on the effects of oestro-
gens on growth. Early researchers found that supraphysio-
logical doses of oestrogens inhibited somatic growth and
from this experience oestrogens, such as ethinyloestradiol in
oral doses of over 200 ng daily, came to be used for the treat-
ment of acromegaly and for the arrest of growth in tall girls.
One study has reported that treatment with conjugated oestro-
gens 7.5 to 11.25 mg daily resulted in average decrease of
about 5 cm from final predicted height. However, treatment
with physiological doses causes growth stimulation, not inhi-
bition, and such physiological doses have been used to pro-
mote growth in girls with conditions such as female
hypogonadism and Turner's syndrome. Oestro-
gen therapy has occasionally been used in girls with delayed
puberty .
Haemorrhagic disorders. Limited evidence supports the
use of oestrogens in various bleeding disorders such as hered-
itary haemorrhagic telangiectasia. and those associated with
chronic renal failure and gastro-intestinal vascular malforma-
tions.
Lactation Inhibition. Synthetic oestrogens (e.g. quinestrol)
and nonsteroidal oestrogens (e.g. stilboestrol) were formerly
employed to suppress lactation . However, such use
is now considered inappropriate because of an increased risk
of puerperal thrombo-embolism.
Premenstrual syndrome. Premenstrual syndrome (PMS)
presents as a variable combination of psychological and so-
matic symptoms occurring during the luteal phase of the men-
strual cycle, which resolve during, and immediately
following, menstruation. A further term. premenstrual dys-
phoric disorder, has been proposed to cover severe cyclical
mood disorder that is functionally incapacitating. Whereas
about 20 to 30% of women have complaints that may be clas-
sified as PMS. only 3 to 5% meet criteria for premenstrual
dysphoric disorder. The term premenstrual tension (PMT)
has sometimes been applied to the psychological symptoms.
Many symptoms of PMS are the same as normal premenstrual
symptoms, but are more severe. Premenstrual syndrome is not
fully understood although it is thought to be due to the
effects of the normal luteal phase release of progesterone on CNS
neurotransmitter function: the syndrome is abolished by sur-
gical or medical suppression of ovarian ftinction. A recent
study has shown that oestrogens, as well as progestogens, can
induce symptoms' Findings from another study demonstrat-
ed that women with PMS may metabolise progesterone dif-
ferently to those without PMS.
Initial management includes non-medical interventions such
as education and support, counselling, stress management,
and relaxation techniques; exercise, and caffeine and salt re-
striction are of unproven benefit. For patients with moderate
to severe symptoms, a number of drugs have been tried with
varying degrees of success; objective assessment of efficacy
has been hampered by varying diagnostic criteria, a marked
placebo response, and difficulties in obtaining reproducible
responses. Treatment may be aimed at modifying the men-
stnial cycle or treating specific symptoms.
In women with predominantly psychological symptoms, in-
creasing evidence suggests that selective serotonin reuptake
inhibitors (SSRIs) may be helpful. Fluoxetine and sertraline have
been shown in controlled trials to alleviate both the
psychological and somatic symptoms in women with pre-
menstrual syndrome. Buspirone, a serotonin receptor agonist.
and clomipramine. a nonselective serotonin reuptake inhibi-
tor, have also been tried with some success. The anxiolytic
alprazolam has also been used, but use of this and other ben-
zodiazepines should be restricted to the luteal phase of the
cycle in selected patients to minimise the risk of dependence
and tolerance.
Abdominal bloating and swelling associated with PMS has
traditionally been thought to be due to sodium and water re-
tention. However, in most women with these symptoms there
is no evidence of an increase in body-weight or in body sodi-
um or total water, and use of diuretics is therefore not justi-
fied. Nevertheless, in women with appreciable weight gain in
the luteal phase diuretics may be useful. Another symptom
of PMS, cyclical mastalgia.
Pyridoxine has been tried on the basis that it is a cofactor in
neurotransmitter (specifically serotonin) synthesis, and has
been found to relieve depression induced by oral contracep-
tives in selected patients. However, its efficacy in premen-
strual syndrome is equivocal, and high daily doses have been
associated with neurotoxicity.
Treatments that modify the menstrual cycle have often been
used in women with PMS. In general, drugs with proven effi-
cacy such as danazol, oestrogen implants, and gonadorelin
analogues are reserved for women with severe PMS unre-
sponsive to other treatments, because of their adverse effects.
Progestogen therapy was once popular, but beneficial re-
sponses have not been universally achieved and the theory
that progesterone was necessary to correct a hormone imbal-
ance is now losing ground. Combined oral contraceptives
have met with limited success and in some women, PMS
is caused or exacerbated by them. Young women with severe
symptoms and women approaching the menopause may ben-
efit from oestrogen delivered either as implants or transder-
maJ patches. In women with a uterus, administration with a
cyclical progestogen is required to avoid endometrial hyper-
plasia which unfortunately, may be associated with the return
of symptoms, although they may be milder. Danazol can be
useful, but there is concern over its adverse effects on lipids
during long-term use and over the risk of masculinisation of a
female fetus should pregnancy occur. For patients with severe
symptoms not amenable to other treatments, gonadorelin an-
alogues such as goserelin can be used to eliminate ovarian
function, 'add-back' treatment with oestrogen plus pro-
gestogen being given to protect against the side-effects of oes-
trogen deficiency including osteoporosis. This treatment is
very effective for both physical and psychological symptoms.
Short-term use (3 months) of a gonadorelin analogue alone
has been used to confirm the diagnosis of PMS. or to predict
the response to bilateral oophorectomy. Immunological
control using an analogue of luteinising hormone-releasing
hormone (LHRH) to raise antibodies against natural LHRH
and thus suppress ovarian function has also been proposed.