Estradiol Pellets

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.^[1] 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. Estradiol is considered to be a product of the ovaries but can also be synthesized 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.^[2]

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.^{[3][4][5][6][7][8][9][10]}

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.^{[11][3][4][5][6][12][13][14][15][16][17][18][19][7][8][9][10]} Regular mammograms are also advised. The link between HRT and breast cancer has been examined.^[20] The Women’s 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].^[21][22] 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].^[23] 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.^{[11][3][4][5][6][12]} 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].^[24] However, an increased risk of ovarian cancer was associated with women utilizing 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.^{[11][3][4][5][6][12]} 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.^{[11][16][20][25]} 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.^{[11][5][8][9]} 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.^{[11][3][4][5][6][12][13][14][15][16][17][18][19][7][8][9][10]} 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.^{[11][3][4][5][6]} 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.^[26] 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.^{[11][3][4][5][6]} 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.^{[11][3][4][5][6]} 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.^[27][28]

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.^[11]

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.^[11] 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 monitoring. 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.^[29][30] Other potential estrogen-related effects for this age group include an increased risk of developing breast cancer and other malignancies, through oral, transdermal, 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.^[17][18][19]

Esterified estrogens e.g. estradiol cypionate and estradiol valerate should be administered intramuscularly.^[7][8] 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.^[4][17][9]

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.^[31] If symptoms of exposure manifest, a healthcare practitioner should be sought.

NOTE: In vitro and in vivo studies indicate that estrogens are partially metabolized by CYP3A4. Interactions with drugs that are inhibitors or inducers of CYP3A4 are possible.

Estrogens may cause amenorrhea, with Bromocriptine typically utilised as treatment for this condition.^[33] Simultaneous administration is not advised. Estrogens have been described to potentially augment calcium absorption and thus positively impact postmenopausal women with osteoporosis. In contrast, this relationship may be detrimental to individuals with susceptibility to hypercalcemia or nephrolithiasis.^[34]

Estrogen and progestin-containing oral contraceptives may decrease the rate of cyclosporin metabolism and subsequent clearance.^[35][36] This may lead to symptoms including seizures, nephrotoxicity and/or hepatotoxicity. Cyclosporins may also elevate plasma estrogen concentrations triggering symptoms such as nausea and breast tenderness.^[37][38] Monitoring is important. Corticosteroid binding globulin (CBG) levels and subsequently corticosteroids in circulation are reported to increase with estrogen use.^[39] An increase in the anti-inflammatory activity of hydrocortisone is linked to estrogen use.^[39] Monitoring is needed when administered concurrently. There is a potential risk of hepatoxicity with the administration of estrogens and dantrolene although the evidence is not clear.^[40][41] A cautious approach should be taken. Before puberty, estrogens are stated to interact with the growth hormones somatropin and somatrem by accelerating epiphysial maturation.^[42]

Estrogens stimulate liver-related synthesis of prothrombin and factors VII, VIII, IX, and X. In contrast, antithrombin III levels decrease.^[38] Data from the Women’s Health Initiative Trials (WHI trials) show a positive relationship between HRT and the risk of thromboembolic disease.^[43] Appropriate labelling is recommended by the FDA in keeping with this observation. HRT is not recommended for individuals with comorbidities including stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis, thromboembolic disease or valvular heart disease. Female patients receiving anticoagulation treatment with warfarin are advised to avoid simultaneous HRT use.^[44] If necessitated, constant monitoring is crucial and should be stopped with the appearance of symptoms.

The safety profile for the use of estrogens in conjunction with tamoxifen is not established and appears to be contraindicated.^[45] Raloxifene’s mechanism of action is to block estrogen receptors (i.e., acts as an antagonist), and hence it would be contradictory to co-administer with estrogen.^[46] Increased antidepressant serum concentrations may potentially occur due to the modulation tricyclic antidepressants metabolism by estrogens.^[47] Cimetidine may potentially decrease the clearance of estradiol and may explain the development of Gynecomastia in individuals receiving cimetidine.^[48][49] Bosentan may interfere with the effectiveness of contraceptives.^[50] It is also teratogenic agent and is not recommended during pregnancy. Modafinil may also compromise the effectiveness of contraceptives as its linked to a decrease in estrogen levels.^[51] Alternative methods are recommended. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin concurrently.^[52] A different contraceptive approach should be assessed as concomitant therapy with oral contraceptives is reported to increase the risk of folate deficiency. Additive effects on folate metabolism may also occur and may elevate the risk of neural tube defects during pregnancy if oral contraceptive fails.^[53]

Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as the carbamazepine family and barbiturates and may augment clearance.^{[54][55][56][57][58][59][60][61][62]} The administration of griseofulvin and oral contraceptives has been reported to compromise the effectiveness of the latter and induce breakthrough bleeding.^[63] Topiramate may potentially increase the removal or clearance of ethinyl estradiol and impact on contraceptive efficacy.^[64] Similarly, Felbamate may potentially augment the removal or clearance of the estrogen component of some oral contraceptives which may impact on efficacy.^[65][66] Alternate contraceptives may be required. Nevirapine may reduce estrogen and other hormones plasma concentrations.^[67] Grapefruit juice may slow down estrogen metabolism.^[34] Effective monitoring of hypoglycaemia in individuals on antidiabetic therapy is paramount.^[34] Hypothyroid patients administered exogenous thyroid treatments may potentially require judicious use of estrogen.^[68] Concurrent use of mineral oil and estrogen may reduce estrogen absorption and thus low estrogen plasma concentration may be observed.^[69] As their respective pharmacologic actions are contrary, estrogen administration is not recommended during aromatase inhibitor treatment.^{[70][71][72][73]} The efficacy of ursodeoxycholic acid may be nullified by estrogen and other hormones.^[74][75]

Soy isoflavones may potentially compete with or have additive effects with, drugs that have estrogenic activity or which selectively modulate estrogen receptors.^[76][77] The relationship is not clear and therefore cautious approach is advised. Unless practicing abstinence, the use of more than one contraceptive (one being non-hormonal) is advised when receiving oral bexarotene therapy.^[78][79] Nefazodone administered with estrogen or other hormones may increase side effects such as nausea and breast tenderness.^[80] Application of sunscreen prior to the application of estradiol topical emulsion increases the exposure to estradiol.^[81]

A subtherapeutic response to metyrapone can be seen in patients on estrogen therapy.^[82] HRT effectiveness may be compromised with simultaneous use of aprepitant.^[83] There is a potential interaction between St. John’s wort (Hypericum perforatum) and estrogens and oral contraceptives as intermenstrual bleeding was observed in some premenopausal women on long term oral contraceptives while utilising St. John’s wort.^[84]

Estrogen plasma concentrations may be elevated with the use of some antibiotics including erythromycin, amiodarone, systemic azole antifungals, clarithromycin.^[37][38] Cautious use of anti-retroviral protease inhibitors and estrogens is advocated as their relationship is not fully characterized or established.

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.^[3] 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.^[11]

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.^[11] 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.^[3] 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.^[85] Physical obstruction of the gastrointestinal tract has been reported with the use of vaginal inserts.^[13]

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.^[86] Some cardiovascular events have been associated with estrogen use. They include deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke.^{[11][3][4][5][6]} 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.^[11][6] 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.^[87] 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 utilizing 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.^[11][6] 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.^[11][6] Insomnia or fatigue may occur.

Dermatological obscuration may occur with estrogen use. Melasma (skin discoloration) 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.^[11][6] Estradiol transdermal systems may potentially result in localized bleeding, bruising, burning, skin irritation, eczema, inflammation, pain, or rash. Paraesthesia has also been reported.^[18] 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 %).^[3] 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.^[6][88] In addition, leg muscle cramps, back pain, arthralgia, and hypocalcemia have been reported.^[11][6] 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.^[89][90][91]

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.^[92] 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.^[3][12][13]

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.^{[20][93][94][95]} 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.

Estradiol cypionate or estradiol valerate injections may cause a reaction locally with symptoms including erythema and mild pain and rarely may cause sterile abscess.^[7][8] 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.^[11][6] 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.

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.^{[11][3][4][5][6]} 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 breastfeeding women. There is also no FDA approval for use as a therapeutic intervention for postpartum engorgement.^[32]

This medication should be stored in its original container at a temperature of 68–77 °F (20–25 °C) and away from heat, moisture, and light. Keep out of reach of children. Discard unused medicine after beyond-use date. Do not flush unused medicines or pour down a drain or sink.

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