Estradiol is pharmacologically classified as an estrogen hormone and it is the main intracellular estrogen in human beings. At cellular levels, Estradiol is many times more powerful than its metabolites; Estriol and Estrone. There are a number of natural sources where Estradiol can be obtained but it can also be prepared synthetically into various salt forms. Estradiol undergoes very fast metabolism and due to this nature, it should be administered as a micronized oral dosage in order to adequately realize its therapeutic effects. The esterification of estradiol into either Estradiol Valerate or Estradiol Cypionate increases the time taken before it reacts which can allow for an intramuscular administration.
Estradiol is mainly used to treat female hypogonadism, to prevent osteoporosis, to relieve the symptoms of menopause and to treat various abnormalities associated with the female gonadotropic dysfunction. In specific circumstances, forms of Estrogen-like estradiol have been used to manage advanced breast cancer in both men and women and also prostatic cancer. The FDA have always allowed the marketing and use of Estrogen products ever since 1938 which was their first year of organization and since then, numerous forms of this medication have been produced and made available for the treatment of the vasomotor symptoms that are associated with menopause.
The use of Estradiol for Hormone replacement therapies has been linked with various negative cases especially an increased risk of endometrial cancer in women with an intact uterus. A combination therapy of estrogens with progestin can reduce this risk but it cannot eliminate it. Additionally, various test studies have indicated that a combination therapy using these two medications can increase a patient’s risk of developing some conditions like myocardial infractions, dementia, strokes and invasive breast cancers. Because of these findings, Estrogens should be prescribed for the shortest time possible and it should be consistent with a patient’s treatment goals.
The ovary is the main source of estrogen hormones in premenopausal women, it secrets about 0.07 to 0.5 mg daily which purely depends on the phase of the menstrual cycle. Estrogens then enter into the cells of responsive tissues like the hypothalamus, the pituitary glands and the breasts/female organs where it increases the rates of protein synthesis. These proteins include the DNA, RNA and other numerous proteins. Estrogens facilitate the growth and development of female sexual organs and female characteristics. They also lead to the proliferation of the endometrium, they increase cervical secretions and facilitate the toning of the uterine walls. The administration of Estrogen leads to a decrease in the production of the gonadotropin releasing hormones which causes a reduction in the secretion of the luteinizing hormones and the follicle stimulating hormones by the pituitary glands. This process can affect various results on ovulation and female reproduction.
Estrogens have very weak anabolic effects, they can accelerate epiphyseal closure and they affect the deposition of calcium in the bones. Various tests have also proven that Estrogens can prevent osteoporosis that is associated with the onset of menopause.
In men with severe prostate cancer, estrogens can help by inhibiting the hypothalamic-pituitary axis through a negative feedback effect which can inhibit some processes. Estrogens will result in a decreased production of the luteinizing hormone and decreased testosterone levels which may alternatively lower the prostate specific antigen levels and reduce the growth rates of the tumor. In the recent past, high doses of estrogen were being used to treat progressive breast cancer in both men and women but ever since the development of selective estrogen receptor modifiers, this practice was abandoned.
The products of Estradiol can be administered orally, intramuscularly, topically or vaginally.
Oral administration. Orally administered Estradiol tablets are usually micronized when they get into the body which slows down their rates of absorption and their effects on the liver. This is one of the factors that leads to the poor bioavailability of Estradiol in the body. After administration, Estradiol is quickly metabolized in the liver and the GI mucosa into Estriol and Estrone. In these forms, it can be circulated in the serum and utilized by the body. The estrogens are then distributed all over the body where they bind to the sex hormone binding globulin and the albumin as they perform their actions. After that, they are conjugated by sulfates and glucuronides into numerous other metabolites which are then excreted through the urine. The half-life of orally administered Estradiol is about 1-2 hours but other circulatory estrogens can last for longer periods.
Intramuscular administration. The two forms of estradiol that can be administered through an intramuscular administration include Estradiol Valerate and Estradiol Cypionate. These are usually given as a depot injection in an oil; formulation which is meant to greatly slow down its rates of absorption. The esterification of estradiol into these two forms is the mechanism used to increase the duration of action in this administration when compared to the administration of other aqueous forms. Cypionate has a longer duration period than Valerate which is averagely 3-6 weeks and 3-2 weeks respectively. Nevertheless, intramuscular doses should be administered at intervals of four weeks and in most cases, the dose is usually adjusted to fit a patient’s needs.
Topical administration. The topical route of Estradiol administration allows for a continuous delivery estrogen because it avoids the first stages of metabolism. Estradiol is hardly metabolized in the skin so when administered through the skin, higher levels of the hormone can be realized and altered to approximate the naturally produced concentrations in the body. The administration of Estradiol through the skin utilizes a micellar non-particle technology which incorporates a 17-beta Estradiol in a soy-based oil formulation. This mechanism is designed to deliver systemic impulses of appropriate levels of Estrogen through the skin and once in the body, it is distributed, it is metabolized and excreted in the same way as that of oral administration.
Vaginal administration. The vaginal mucous membrane is a very good spot for the administration of Estradiol. An intravaginal ring can be used to deliver adequate doses of Estradiol to a patient in less than one hour. Vaginal administration also avoids the first pass metabolism which ensures that the concentration of Estradiol that is absorbed into the body is higher than through other methods of administration. Once absorbed into the body, its distribution, metabolism, and excretion occur in the same way as that of oral administration.
Estradiol is primarily indicated for relieving moderate to severe symptoms of menopause such as vaginal dryness, flashes, irritation and burning sensations. It is also indicated as a maintenance therapy for the treatment of postmenopausal atrophic vaginitis, ovarian dysfunctions, various types of ovarian cysts, female hypogonadism, atrophy of the vulva and in selected cases, as a treatment for breast cancer in both men and women.
Contraindications and precautions when using Estradiol.
Estradiol sprays and topical gels are alcohol based so they are potentially flammable. Patients are advised to avoid flames and fire until these applications have been completely absorbed.
The esters of Estradiol i.e. Valerate and Cypionate, are oil based and they should never be administered through intravenous injections. Instead, they should be intramuscularly administered.
All estrogens are contraindicated in patients with any cases of breast cancer, both known and unconfirmed.
Estrogen influences the metabolism of calcium and phosphorus so Estradiol is not recommended for patients with hypercalcemia especially that which is associated with metabolic bone diseases or tumors.
Estradiol should be used cautiously in patients with endometriosis or uterine leiomyomata/fibroids because they can accelerate the growth of fibroids.
Estradiol is contraindicated in women with undiagnosed and abnormal vaginal bleeding because this may be due to malignant growths which can lead to worsening of the situation.
Estrogens are contraindicated in any medical conditions that are associated with the presence of tumors that can respond to estrogen. It should be used with care and caution in patients with variegate hepatic porphyries since it can worsen this condition and because of some surgical procedures that can increase the risks of thromboembolism, the administration of estrogen should be discontinued for several weeks before a major surgery where possible. This can be 4-6 weeks before the surgery.
Estrogens should be used cautiously in patients with hypogonadism and other diseases of the thyroid glands. Estrogens are never indicated for infants because they promote epiphysial closure which can lead to adverse and abnormal effects on children.
Estrogens should never be administered during pregnancy because it can lead to the development of an abnormal fetus. It should also be used cautiously in lactating and breastfeeding mothers and the baby should be monitored very closely to check for any side effects and ensure safety.
Numerous studies have indicated that Estrogens can be metabolized by CYP3A4 so it can safely interact with CYP3A4 inducers or inhibitors where inevitable.
Bromocriptine is indicated for the restoration of ovarian functions and ovulation in amenorrhoeic women. Estrogens can cause amenorrhea and counteract the effects of this medication, so they should not be used together.
Estrogens increase the absorption of calcium so the interaction of Estradiol and calcium salts can be beneficial especially in postmenopausal women with osteoporosis but it is not recommended in women with nephrolithiasis or hypercalcemia.
Estrogens have been associated with elevating the levels of corticosteroid-binding globulin which may lead to increased levels of this protein circulating the system. Its clinical significance has, however, not been established.
Estrogens should never be used together with dantrolene because this might increase an individual’s risk of hepatotoxicity.
There is a lot of controversy surrounding the use of Estrogens with tamoxifen but generally, it is contraindicated in most circumstances.
Raloxifene acts by blocking estrogen receptors so concurrent use is illogical.
Bosentan should not be administered together with estrogen products since it can lead to contraceptive failure. Additional methods of contraception can be incorporated for more sure results. Alternative methods of contraception should also be considered when using modafinil therapy with the administration of estrogen.
Estrogens can interfere with the pharmacological action of aromatase inhibitors so concordant use is not recommended.
Other medications that should not interact with estrogen products include; topiramate, Felbamate, Nevirapine, Exogenous thyroid treatments, Mineral oils, ursodeoxycholic acid, Nefazodone, aprepitants and fosaprepitant, Erythromycin, Systemic azole antifungals, Conivaptan and antiretroviral protein inhibitors.
It is very important to administer this medication with a lot of caution and close monitoring especially during its co-administration with contraceptives and other medications. Make sure that you inform your health service provider of all the medications that you are currently on and the drugs that you are using.
Many of the adverse reactions that have been reported from the use of Estradiol are very similar to those associated with the use of other estrogen products. These risks are potentially lower during postmenopausal administration compared to premenopausal use because of lower levels of estrogen in the body during this period. Some of its side effects can include; changes in libido, which can be positive or negative depending on your moods, vaginal discharge, vaginitis, cervicitis and changes in vaginal erosion.
Breast pains (Mastalgia), are also very common and they may be accompanied by breast enlargement, breast tenderness, breast discharge and some fibrocystic breast changes. Patients should report any breast changes to their health care providers so that they can have physical examinations to rule out any possible tumors.
Other effects of estradiol can include; abdominal/stomach pains, bloating, vomiting and nausea. Venous thrombosis, myocardial infarction, strokes and pulmonary embolism are also some conditions that can be developed with prolonged use.
Estradiol and other estrogens can cause fluid and sodium retention in the body which might lead to mild weight gain and peripheral edema.
A severe headache after administration can be a sign/ a warning of a serious medical effect such as a stroke or retinal problems. This relationship is not clearly defined but in a case of a severe headache, a patient should contact health care services immediately.
Special care and close monitoring should be given to patients with a history of depression since estrogens can worsen this condition.
During treatment, some women can experience tenderness, swelling or bleeding of the gums which can be associated with gingivitis, for this reason, proper medical attention should be sought.
Estrogen therapy can worsen endometrial hyperplasia. A combination therapy of estrogen and progestin can increase a patient’s risk of developing urinary incontinence especially in women with a history of heart diseases.
This drug should be applied daily at the same time to a clean, dry and intact part of the skin preferably on the upper arms or shoulders. All instructions should be followed on administration according to your physician. You should never mix this medication with deodorants or other products, always allow it to dry off completely before putting on your clothes.
In case you miss a dose, make sure that you apply it as soon as you remember and never take two doses or an overdose. Keep all your medicine away from the reach of children.
The dosage form available for Estradiol in our pharmacy is a transdermal cream but our pharmacy can compound this medication in any other form and dosage that will work best for any patient. For more information about this medication and its administration, feel free to contact us.