Multiple Strengths

Estradiol (also known as 17β-estradiol or E2) is the most abundant and potent (due to superior affinity for the estrogen receptor) of all estrogens. The other estrogen types include estrone (E1), estriol (E3), estetrol (E4). Estrone is produced in the adrenal gland from the precursor androstenedione and thus its levels remain unchanged post-menopause. Estriol (E3) is produced during pregnancy in the placenta and found at lower levels in comparison to estradiol or estrone in non-pregnant individuals. Estradiol is considered to be a product of the ovaries but can also be synthesised extraglandulary. Extraglandulary production has been reported to occur in tissues and organs for example skin, adipose tissue, brain, and bone via the expression of the enzyme aromatase which converts androstenedione and testosterone to estradiol. Since the ovaries are considered the predominant site of production of estradiol, decreased levels of this hormone is concurrent with the onset of menopause in women due to low-functioning ovaries. Circulating estradiol levels in pre-menopausal women range from 40 pg/mL to 200–400 pg/ml across the menstrual cycle. Post-menopause, this hormone concentration decreases to approximately less than 20 pg/ml. Subsequently, menopausal symptoms such as vulvovaginal atrophy, dyspareunia, hot flashes, and night sweats ensue. In addition, the depletion of estradiol is also implicated in a variety of pathophysiological processes including postmenopausal bone loss (osteoporosis), and cardiovascular disease such as coronary heart disease. The natural decline of estradiol presents an opportunity for the use of exogenous sources of this hormone to supplement and restore depleted reserves. Hormonal supplements are typically prescribed as a therapeutic intervention to minimise the emerging symptoms and effects of menopause. These estrogens can be obtained from biological sources or through synthetic mediums. In addition to the treatment of menopausal symptoms, estrogen is FDA-approved as a therapy for other conditions such as primary ovarian insufficiency, female hypogonadism, moderate acne vulgaris, and prostate cancer with advanced forms of metastasis. It is also utilised as an oral contraceptive pill (the synthetic estrogen, ethinyl estradiol is commonly prescribed). Other synthetic steroid estrogens include estradiol valerate, estropipate, conjugate esterified estrogen, and quinestrol. Examples of nonsteroidal synthetic estrogens include dienesterol, diethylstilbestrol, benzestrol, methestrol, and hexestrol.

Estrogen in circulation can passively diffuse across a cell membrane and into a cell as it is a steroid hormone. Subsequently, estrogen acts as a ligand and binds to estrogen receptors (ERs) that are located in the cytoplasm. There are two types of ERs namely ER-alpha (ER-α) and ER-beta (ER-β). The binding of estrogen to ERs induces a conformational change in the latter and the estrogen-ER complex translocates to the nucleus and bind to DNA resulting in the modification of gene transcription. This alteration results in the synthesis of proteins that are able to influence downstream physiological processes. In addition to affecting physiological processes, estrogen’s role also extends to pharmacological functions. In the former, the ubiquitous role of estrogen can be observed.

Breast: Estrogen induces the proliferation of glandular and ductal tissue in the breast and promotes alveolar growth. This results in the development of the breast tissue during puberty, commencement of ovulation, and ovarian synthesis of estriol.

Genital tract: Estrogen encompasses an important role in maturing the female sexual characteristics and in the development of epithelial lining of the vagina and uterus. This is crucial in the regulation of the menstrual cycle in premenopausal women.

Vagina: Estrogen has a key role in promoting the proliferation of epithelial mucosa cells of vagina and vulva. Insufficient levels of estrogen may result in a condition known as vulvovaginal atrophy whereby the epithelial mucosa cells of the vagina and vulva becomes thin and symptoms manifests as dryness.

Bone: Estrogen provides support in the development of long bones and fusion of the epiphyseal growth plates. Insufficient levels elevate the risk of a fracture in postmenopausal women as a result of a decrease in bone reabsorption and an increase in bone mineral density. Estrogen exerts protective effects by inhibiting the activities of osteoclasts resulting in the prevention of osteoporosis in both estrogen-deficient and post-menopausal women.

Cardiovascular: Estrogen increases the amount of HDL cholesterol and triglycerides while decreasing the amount of LDL cholesterol and total plasma cholesterol. This aids in reducing the risk of coronary artery disease in early use in postmenopausal women.

Some pharmacologic functions of estrogen are explored below:

Contraception: Estrogen is used as contraception. Ethinyl estradiol suppresses ovulation during the menstrual cycle by inhibiting the hypothalamus release of gonadotropin-release hormone (GnRH) and pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

Hormone replacement therapy (HRT): Estrogen is typically used to treat menopausal symptoms, deter the onset of osteoporosis and minimise the risk of cardiovascular disease without elevating the risk of uterine cancer, ovarian cancer, or breast cancer. The goal is to have sufficient estrogen bioavailability and receptor selectivity in order to be effective. Due diligence in terms of assessing the therapeutic agent’s mechanism of action, the potential for adverse effects, and contraindications should be performed prior to selecting and administering a specific HRT. Several types of HRT exist including conjugated equine estrogen (CEE), synthetic estrogens, estrogen-androgen combination therapy, and vaginal preparations.

Estrogen can be administered as a therapeutic intervention via multiple routes of administration with distinct dosages as depicted.

Oral: Estrogen (with dosage between 0.3–1.25 mg), estradiol (0.5–2 mg), Norethindrone/ethinyl estradiol (1.5 mg/30 µg).

Transdermal: can be applied via topical spray (Estradiol topical spray applied to the inner surface of the forearm: 1.53 mg/actuation), topical cream (Estradiol topical gel (0.006%): 0.52 mg/pump), vaginal cream (Estrogen, conjugated vaginal cream: 0.625 mg/g applied intravaginally), transdermal patch (Estradiol transdermal patch (dosage ranges between 0.025– 0.1 mg daily))

Vaginal Ring: Estradiol vaginal ring to treat vulvovaginal atrophy (7.5 µg per day). Combination therapy estrogen-etonogestrel/ethinyl estradiol hormone vaginal ring for contraception (dose of 0.12 mg/0.015 mg daily).

Intramuscular Injection: Estradiol valerate (dosage of 10–40 mg/mL) for vasomotor symptoms of menopause, vulvovaginal atrophy, and hypoestrogenism. For advanced prostate cancer, palliative treatment consisting of more than 30 mg is recommended. Estradiol cypionate (dosage of 5 mg/mL) utilised as therapy for menopausal symptoms.

The route of administration is an important variable that influences the levels of estrogen that is biologically available to an individual. Common administration routes include oral, transdermal, and vaginal.

Oral: There are two predominant mechanisms whereby estrogen is metabolised: (1) via metabolism to the biologically active but less potent estrone or estriol, (2) via conjugation into water-soluble and nonbiologically active metabolites for excretion. In the former mechanism, the gut and liver rapidly breaks down orally ingested estrogen prior to reaching circulation and is known as the first-pass effect. This subsequently results in a reduced concentration of estrogen available for use in circulation. This process has been stated to impact on other liver functions and may explain the observation of different lipid profiles as a function of administration route. For example, an increased level of HDL cholesterol is observed with orally ingested estrogens. In contrast, a decreased level of HDL cholesterol is observed when estrogen is administered transdermally. In the mechanism of conversion to nonbiologically active metabolites, estrogens are conjugated or modified to be water soluble by the liver and subsequently transported to the gastrointestinal (GI) tract via the bile ducts. In the intestines, the normal flora may unconjugate and modify the estrogen to be lipid-soluble again and biologically active. This biologically active form can then be re-absorbed into circulation via the entero-hepatic system. The effectiveness of oral contraceptives whilst also on an antibiotic regimen may be compromised as antibiotics can impact on the intestinal microflora and thus reducing the levels of biologically active estrogen available for re-absorption into general circulation. This limited quantity of active estrogen may be insufficient to suppress ovulation. This occurrence is more likely in women that are administered rifampin resulting in cytochrome P450-mediated hormonal contraceptive metabolism in comparison to those on ampicillin or tetracycline.

Transdermal: Estrogen enters systemic circulation from an estrogen-containing patch through the skin. Since the percentage of systemic blood flow to the liver is approximately 10–20 %, a considerable amount of the estrogen is not metabolised by the liver resulting in a higher bioavailability compared to the oral route of administration with the drug entering from the stomach in which approximately 60–90 % can be metabolized from first pass. An advantage of this method is the reduction of the risk of patient noncompliance as the need for repeated doses within a day is minimised.

Vaginal: Estrogen vaginal administration is stated to be well absorbed and high local concentrations can be achieved with low concentrations available systemically, although the latter may increase with increasing dosages. In addition, distinct products yield varying systemic concentrations, and several products are not recommended to treat systemic conditions or prevent osteoporosis. In an open-label, multiple-dose, parallel group study conducted in 58 patients who were administered 10 µg Vagifem (an estradiol vaginal insert) daily for 2 weeks, followed by a twice-weekly maintenance regimen for the remaining 10 weeks, a mean estradiol concentration of 5.5 pg/mL was observed at day 83. An identical regimen with 25 µg Vagifem yielded a mean estradiol concentration of 11.59 pg/mL at Day 83.

Special Populations:

Hepatic Impairment: Limited data exists with regards to the pharmacokinetic pathway of individuals with hepatic impairment. The liver has a crucial role in facilitating estrogen metabolism, and thus estogen may not be effectively metabolised in patients with a defective liver or liver-related issues. Estrogens should not be administered to patients with severe hepatic pathophysiological conditions.

Renal Impairment: Limited data exists with regards to the pharmacokinetic pathway of individuals with renal impairment. When administered oral estrogen, the total estradiol serum concentrations in postmenopausal women with end stage renal disease (ESRD) receiving hemodialysis are higher in comparison to healthy subjects at baseline. Subsequently, routine transdermal estradiol administration may be excessive for renal compromised patients and attention to dosage and patient response should be monitored.

Pediatrics: The availability of data with regards to products available to young individuals including children and adolescents is limited. Typical routes of estrogen administration are systemic and transdermal mediums. An approach to selecting a start dose for individuals in this population involve the following recommended guidelines, which includes prescription of a fraction of adult administered estrogen dosages (one-tenth to one-eighth) combined with prior knowledge of the prescribed formulation.

Estradiol is contraindicated in individuals with previous experience of anaphylactic reactions or angioedema in relation to estradiol products and further use is not advised. Previous reported cases show that the patient response can occur in minutes and may require immediate medical intervention. Individuals with hereditary angioedema may experience more intense symptoms. Estradiol products are contraindicated in neoplasms which include breast, ovarian, and endometrial cancers that are estrogen-dependent. Abnormal mammograms have been observed for women using estrogen-alone or estrogen-progestin treatment. Monthly breast self-examination and annual clinical assessment is recommended when undergoing hormonal therapy. Regular mammograms are also advised. The link between HRT and breast cancer has been examined. The Womens Health Initiative (WHI) clinical trial is a benchmark randomized study that provides valuable insights into the interaction of breast cancer and hormonal therapy. An increased risk of breast cancer was not observed in patients receiving daily estrogen-only treatment vs. placebo after a mean follow-up of 7.1 years [relative risk (RR) 0.80]. However, an elevated risk of invasive breast cancer was observed when undergoing daily estrogen-progestin treatment vs. placebo after an average follow-up of 5.6 years [relative risk (RR) 1.24]. The risk of invasive breast cancer was observed to be elevated in women with previous hormonal therapy [relative risk (RR) 1.86] undergoing estrogen-progestin treatment. The relative risk was lower [relative risk (RR) 1.09] for individuals undergoing the same treatment but had no prior hormonal therapy. Invasive breast cancers were observed to be larger, increased probability to be node positive, and were diagnosed at a more advanced stage in the HRT cohort vs. placebo. Likelihood of metastasis is slim. Histologic subtype, grade and hormone receptor status did not differ between the two cohorts. Other observational studies are in congruent with the WHI study in terms of reporting the differing risks of invasive breast cancer with respect to the distinct hormonal treatments. The influence of other factors such as route of administration, dose, and types of estrogen-progestin treatment on the risk of invasive breast cancer is yet to be elucidated. In the rare case in which estrogen is used as palliative treatment for advanced breast and bone cancers, it should be noted that hypercalcemia may ensue and treatment should cease if this occurs, and counteracting measures be implemented to restore calcium levels. In the same benchmark study, a statistically non-significant result was observed for an increased risk of ovarian cancer when patients receiving estrogen-progestin treatment were compared to placebo after a mean follow-up of 5.6 years [relative risk (RR) 1.58] However, an increased risk of ovarian cancer was associated with women utilising hormonal therapy for menopausal symptoms after meta-analysis of 17 prospective and 35 retrospective epidemiology studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.5). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The link between risk and duration of HRT use is yet to be reported. Unopposed estrogen treatment is linked with endometrial hyperplasia in women with an intact uterus which may potentially result in the development of endometrial cancer. The addition of progestin has been shown to decrease the risk of endometrial hyperplasia. Cases of endometrial hyperplasia have been reported postmarketing in estrogen-alone users. The risk of endometrial cancer is reported to be approximately 2–12 greater in comparison to non-users and appears dependent on duration of treatment and on estrogen dose although several studies show no significant increased risk associated with use of estrogens for less than 1 year. Extended use impacts greatly with increased risks of 15- to 24-fold for 5–10 years or potentially more with effects still observed after the treatment has ceased. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of comparable dosage. Increased risk of ovarian cancer is also associated with HRT use. Furthermore, estrogens are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Strict monitoring is recommended for all individuals on hormonal therapy which includes participation in clinical screening and examinations as needed. Caution is advised. Some cardiovascular events have been associated with estrogen use. They include deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke. Individuals should cease treatment and seek a qualified healthcare practitioner if symptoms are observed. Estrogen therapy is not suggested for use in individuals with confirmed thrombophilic diseases such as protein C deficiency, protein S deficiency as the risk of venous thrombosis is elevated. Attention to other risk factors is also paramount. Furthermore, a link between estrogen use and an elevated risk of thromboembolism has been shown. In the WHI study, patients receiving daily estrogen monotherapy displayed increased risk of venous thromboembolism vs. the placebo cohort. Furthermore, patients receiving estrogen-progestin displayed a statistically 2-fold increase in the risk of VTE vs. placebo. Estrogens with or without progestins is not recommended as a preventative measure for cardiac or cardiovascular disease. Estrogen was associated with an increased risk for stroke in patients (50–79 years old) receiving either daily estrogen monotherapy or combined estrogen-progestin combination treatment vs. placebo. Increased blood pressure has been observed in a few patients with hypertension and requires close monitoring although a large, randomized, placebo-controlled clinical trial, did not observe alterations in blood pressure with estrogen administration. Estrogen therapy may result in sodium and fluid retention and susceptible individuals should be identified and closely monitored when receiving estrogen treatment. In male breast or prostate cancer patients treated with estrogens for palliative care, increased risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitiss has been observed. For scheduled surgeries with risk of thromboembolism, estradiol treatment should not be administered within 4–6 weeks of the surgery. This also applies to individuals with prolonged inactivity. Return to treatment will be considered after assessment of all risk factors. Estrogens can diffuse unopposed from the placenta to the fetus. Estrogen prescription is not recommended during pregnancy. For women that unknowingly use estrogen- or progestin-containing products, the risk of birth defect in their children is not increased or minimal. Some studies have reported that the continuous use of estrogens by pregnant women may elevate the risk of developing fetal anomalies such as limb defects, cardiovascular and sexual organs development abnormalities. Estradiol has been used in conjunction with clomiphene in specific cases to treat infertility, or in donor oocyte procedures. Subsequently estradiol administration is stopped upon the development of pregnancy. There is evidence that estrogen therapy may reduce breast milk levels and quality and is not recommended for use in breast-feeding women. There is also no FDA approval for use as a therapeutic intervention for postpartum engorgement. Estrogen use is not recommended for individuals with liver-related malignancies or diseases. Liver impairment is associated with poor estrogen metabolism. In addition, individuals with history of cholestatic jaundice are advised to exercise caution. This advice also applies to individuals with variegate hepatic porphyria and a history of gall bladder disease. Patients with systemic lupus erythematosus (SLE) are advised to exercise caution with regards to the use of estrogen therapy due to an increased risk for thromboembolism. Estrogen and potentially other hormones are suspected to have a role in the pathophysiology of SLE since the majority of individuals diagnosed with this condition are women. The literature contains contradicting results with one study reporting a link between HRT and lupus, and others with distinct conclusions. It will be important to elucidate the mechanism of this interaction as estrogen therapy is known to be beneficial in managing symptoms of menopause in postmenopausal women. In addition, there is an increased risk of venous thromboembolism women with hypercoagulable states when undergoing HRT. This state is common in SLE patients and may result in a rise of strokes, heart attacks, and blood clots cases in individuals receiving HRT. The SELENA trial, a large prospective, randomized clinical trial evaluating the safety of estrogen therapy (both as oral contraceptives and HRT in postmenopausal women) in patients with SLE has been completed and is being analysed. This would aid in gaining more understanding. In women with a history of hypertriglyceridemia, estrogen treatment is potentially linked with increased plasma triglycerides culminating in pancreatitis. Therapy should be stopped if this develops. Some cases have reported retinal vascular thrombosis with estrogen use. Cease therapy upon the onset of severe headache or partial/complete loss of vision and seek a qualified healthcare practitioner. If the clinical assessment indicates papilledema or retinal vascular lesions, then estrogen use should be permanently stopped. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses. The risk of thromboembolism may be increased in patients predisposed to arterial vascular disease and are receiving estradiol treatment and thus monitoring is required. Judicious use of estradiol is advised for thyroid disease patients especially individuals with hypothyroidism as estrogens may elevate the concentration of thyroid-biding globulin (TBG). Individuals with functioning thyroid can counteract this by increasing the production of thyroid hormones. For individuals without this capacity and require exogenous thyroid hormone supplements, an elevated dose may be required and should be monitored. Estrogen therapy may result in fluid retention and affect certain individuals. Aggravation of conditions such as asthma, seizure disorder, and hepatic hemangiomas has also been reported and cautious use of estrogen therapy is advised. Similarly, exacerbation of mood disorders has been linked to estrogen treatment and requires close monitoing. If mood disturbances persist, the treatment should be stopped. Hormone therapy treatment is not recommended to women aged ≥ 65 years old due to an increased risk of dementia. Other potential estrogen-related effects for this age group include an increased risk of developing breast cancer and other malignancies, through oral, trasndermal, and other systemic administration of estrogen therapy according to the Beers Criteria. Estrogen vaginal administration is considered safe and effective for treating menopausal symptoms including vaginal dryness and other vagina/vulvar symptoms. Individuals with urinary incontinence should avoid estrogen treatment to avoid possible exacerbation. Data depicting the safety and efficacy of estrogen is not established in neonates, children or infants. This hormone promotes epiphyseal closure and bone maturation. Nausea and vaginal withdrawal bleeding (in female children) has been associated with high doses. Estrogen treatment has also been administered to promote puberty in some adolescents. Esterified estrogens e.g. estradiol cypionate and estradiol valerate should be administered intramuscularly. Intravenous administration may cause serious adverse effects. Estradiol topical gels and sprays contain alcohol and are potentially a fire hazard. Hence flammable conditions such as fire, flame, or smoking should be avoided during application. There is potential of accidental exposure of estrogen treatment to others and awareness is necessary. For example in 2010, the FDA reported an advisory notice for Evamist brand topical spray secondary exposure through skin contact. Safety data sheets should be checked. Adverse events such as premature puberty, nipple swelling and breast development in females and breast enlargement in males have been reported. Reports of pet exposure were also reported with nipple enlargement and/or vulvar swelling observed. The risk of exposure to others can be mitigated by avoiding contact with the treated section or by covering up the area. Upon accidental exposure, the contaminated area should be washed with water and soap. If symptoms of exposure manifest, a healthcare practitioner should be sought.

Estrogens can diffuse unopposed from the placenta to the fetus. Estrogen prescription is not recommended during pregnancy. For women that unknowingly use estrogen or progestin from oral contraceptives, the risk of birth defect in their children is not increased or minimal. Some studies have reported that the continuous use of estrogens by pregnant women may elevate the risk of developing fetal anomalies such as limb defects, cardiovascular and sexual organs development abnormalities. Estradiol has been used in conjunction with clomiphene in specific cases to treat infertility, or in donor oocyte procedures. Subsequently estradiol administration is stopped upon the development of pregnancy.

There is evidence that estrogen therapy may reduce breast milk levels and quality and is not recommended for use in breast-feeding women. There is also no FDA approval for use as a therapeutic intervention for postpartum engorgement.

Estradiol therapy may exert some unintended consequences. For example changes in sexual appetite (both positive and negative changes) have been reported. The positive changes may be due to improvements to the vulvovaginal atrophy. Vulvovaginal infections may occur; a study reported the development of vulvovaginal mycotic infection in 8 % of patients administered estradiol therapy vs. 3 % that were given placebo. In women with fibroids, estrogen may cause an increase in their size. A condition akin to cystitis has been highlighted. Abnormal vaginal bleeding has also been reported in some cases. Persistent bleeding may require further assessment by a qualified healthcare practitioner. Persistent amenorrhea in premenopausal women treating hypogonadism using estrogen may require further assessment. Adherence to guidelines of routine evaluations for individuals on estrogen therapy is important.
A recurrent reported side effect of estrogen therapy is mastalgia (also known as breast pain). In addition, breast tenderness, enlargement, discharge, galactorrhea, and fibrocystic breast changes have been reported. Gynecomastia may manifest in men. Individuals should self-examine and present themselves to a qualified healthcare practitioner upon noticing changes. Depending on other variables such as risk factors, and age, mammography assessments can be incorporated. Other common unwanted effects are stomach or abdominal pain, bloating, nausea, and vomiting which may cease as the regimen progresses. Diarrhea may occur as seen in a clinical study in which 5 % of patients receiving estradiol vaginal therapy had diarrhea in comparison to 0 % in the placebo group. Oral contraceptives have been linked to the development of benign hepatic adenomas, and an enlargement of hepatic hemangiomas. The former may be plausible with the presence of abdominal pain, abdominal mass or hypovolemic shock. Pancreatitis, colitis, cholestatic jaundice, and gallbladder disease have also been reported in some cases. Physical obstruction of the gastrointestinal tract has been reported with the use of vaginal inserts.
Individuals with impaired liver function should exercise caution due to poor metabolism of estrogens. Rare adverse reactions include hepatitis and peliosis hepatis. The latter as a result of taking estrogens and combined oral contraceptives. Some cardiovascular events have been associated with estrogen use. They include deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke. Individuals should cease treatment and seek a qualified healthcare practitioner if the symptoms are observed. Estrogen therapy may result in sodium and fluid retention, resulting in peripheral edema or mild weight gain and may cause harm to certain individuals. Elevated blood pressure which may cause hypertension has been reported. A large, randomized, placebo-controlled clinical trial, did not observe alterations in blood pressure with estrogen administration. However the PEPI trial, showed an increase in blood pressure in postmenopausal women after hormone replacement therapy in comparison to the placebo group although this difference was not statistically significant. It is recommended that blood pressure be monitored with estrogen use.
Headache only has also been associated with estrogen therapy accounting for 5–7 % of reported side effects in dyspareunia patients utilising estradiol vaginal inserts. Headache with no other symptoms occurred at an average incidence range of 5–21 % with various systemic and transdermal estradiol treatments in postmenopausal women. This could be an indicator for major adverse occurrences such as a stroke or eye thrombosis. Cease therapy upon the onset of severe headache or partial/complete loss of vision and seek a qualified healthcare practitioner. Mental depression, nervousness or anxiety, mood disturbances have been linked with estrogen use and treatment should stop following an increase in severity hence monitoring is important. Insomnia or fatigue may occur.
Dermatological obscuration may occur with estrogen use. Melasma (skin discolouration) may develop facially. The severity of existing conditions such as acne vulgaris may increase. Other conditions such as Erythema multiforme, erythema nodosum, alopecia (loss of scalp hair), hirsutism, pruritus, maculopapular rash, and, angioedema have been reported. Estradiol transdermal systems may potentially result in localized bleeding, bruising, burning, skin irritation, eczema, inflammation, pain, or rash. Paraesthesia has also been reported. Estradiol vaginal therapy with estradiol may result localized itching or irritation; with a clinical trial reporting an increase in vaginal itching incidence in patients administered vaginal tablets (8 %) vs. placebo (2 %). Dental effects such as tenderness, swelling, or minor bleeding of their gums has been reported in some cases and monitoring is recommended.
Hyperglycemia has been reported in some cases with estrogen use and thus judicious use in diabetic patients is advised. In addition, leg muscle cramps, back pain, arthralgia, and hypocalcemia have been reported. Estrogen only and combination therapeutic approaches are linked with the risk of developing dementia in women aged ≥ 65 years old. In a clinical study (Women’s Health Initiative Memory Study (WHIMS)), 4532 postmenopausal women were randomized to receive a combination of estrogen and progestin or placebo daily. An average follow-up of 4 years indicated that 40 women in the treatment group and 21 women in the placebo group were diagnosed with probable dementia. In the WHIMS estrogen-alone ancillary study, 2947 hysterectomized women were randomized to receive estrogen-alone or placebo daily. An average follow-up of 5.2 years indicated that 28 women in the treatment group and 19 women in the placebo group were diagnosed with probable dementia.
The risk of developing urinary incontinence is elevated in women with a history of cardiovascular disease with HRT use. In the HERS study, women that received estrogen/progestin treatment were almost twice as likely and 3 times as likely to develop urge incontinence and stress incontinence respectively after a year. This was more noticeable with time.
Toxic-shock syndrome (TSS), as a result of bacterial infection has been reported in women using vaginal rings containing estradiol. Symptoms of this condition include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, fainting, or a sunburn-rash on the face and body. Seek medical advice immediately. Other reported events include adherence to bladder and/or vaginal wall. Surgery may be required for removal. Vaginal or bladder wall erosion may occur with use of the vaginal rings. Symptoms include individual or combined manifestations of vaginal pain or irritation, abrasion, and spotting. Seek medical advice with emerging symptoms.
Unopposed estrogen treatment is linked with endometrial hyperplasia in women with an intact uterus which may potentially result in the development of endometrial cancer. The addition of progestin has been shown to decrease the risk of endometrial hyperplasia. Cases of endometrial hyperplasia have been reported postmarketing in estrogen-alone users. The risk of endometrial cancer is reported to be approximately 2–12 times greater in users in comparison to non-users and appears dependent on duration of treatment and on estrogen dose although several studies show no significant increased risk associated with use of estrogens for less than 1 year. Extended use impacts greatly with increased risks of 15- to 24-fold for 5–10 years or potentially more with effects observed after the treatment has ceased. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of comparable dosage. Data from the Women’s Health Initiative (WHI) study suggests an increase in the risk of invasive breast cancer in patients administered an estrogen-progestin combination in comparison to the placebo group. Similarly, the risk of breast cancer development may increase with duration of use. Hypercalcemia may be seen in breast and bone cancer patients. Increased risk of ovarian cancer is also associated with HRT use.
Estrogen prescription is not recommended during pregnancy. For women that unknowingly used estrogen or progestin from oral contraceptives, the risk of birth defect in their children is not increased or minimal. Estradiol cypionate or estradiol valerate injections may cause a reaction locally with symptoms including erythema and mild pain and rarely may cause sterile abscess. Estrogens are known to cause congenital malformations with continued use during pregnancy. These include altered development of sexual organs, cardiovascular and limb abnormalities have been reported. The use of diethylstilbestrol is known for creating disturbances in the reproductive systems of both male and female offspring.

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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Panama City	Miramar	Boca Raton	Jupiter
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