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Estrogen therapy is a form of hormone replacement therapy used to manage symptoms associated with menopause, including vasomotor symptoms such as hot flashes and genitourinary syndrome of menopause, which encompasses vaginal dryness and dyspareunia. A decline in ovarian estrogen production during menopause contributes to these symptoms, significantly affecting quality of life. Estrogen therapy is administered alone in patients who have undergone hysterectomy, whereas patients with an intact uterus require combined estrogen-progestin therapy to prevent estrogen-induced endometrial hyperplasia. This activity focuses on estrogen therapy without progestin, addressing indications, mechanism of action, administration methods, adverse effects, contraindications, monitoring, and toxicity.
A detailed understanding of estrogen therapy supports clinical decision-making by allowing for individualized treatment strategies while minimizing risks. This activity provides healthcare professionals with essential knowledge to optimize estrogen therapy administration, improve patient outcomes, and maintain high standards of care in hormone therapy.
Estrogen therapy (ET) is a form of hormone replacement therapy (HRT) administered to mitigate the uncomfortable symptoms that often accompany menopause.
[1] Menopausal hormone therapy (MHT) may also be referred to as postmenopausal hormone therapy or hormone replacement therapy. Roughly 1.5 million women between the ages of 45 and 55 experience menopausal symptoms, including vasomotor symptoms such as hot flashes and night sweats. Additional symptoms include irritability, mood and sleep disturbances, fatigue, decreased libido, dyspareunia, and atrophic vaginitis. The results of the Women's Health Initiative trial have indicated that estrogen therapy is ineffective at preventing vasomotor symptoms, osteoporosis, and cardiovascular diseases.
Although estrogen therapy remains a controversial treatment in symptomatic menopausal women due to the risks potentially outweighing the benefits, there is a definite need for estrogen therapy in women experiencing distressing symptoms, particularly the non-systemic form. Without this therapy, a third of women experience itching, irritation, dryness, and dyspareunia that negatively impact their quality of life. Localized estrogen treatment often relieves these symptoms and significantly increases the quality of life, including life-changing improvements in sexuality, the incidence of urinary tract infections, and incontinence.
[2] The method of estrogen delivery is vital for assessing its benefits and uses. In stark contrast to oral formulations, the administration of transdermal estrogen has been linked to a lower risk of deep vein thrombosis, cholecystitis, osteoporosis, and stroke. Long-term estrogen therapy has also proved beneficial in a patient with an increased risk of osteoporotic fractures. The main estrogens are estrone (E1), estradiol (E2), and estriol (E3).
[3] The estrogen formulations with FDA-approved indications are listed below.
FDA-Approved Indications
Oral estradiol: Oral estradiol is FDA-approved for moderate or severe vasomotor symptoms and vulvovaginal atrophy associated with menopause. When prescribing solely for vulvar or vaginal atrophy, topical vaginal products should be considered. For postmenopausal osteoporosis prevention, oral estradiol treatment should be considered only for women at significant risk and when non-estrogen options are unsuitable.
Oral esterified estrogen: Esterified estrogens are a mixture of sodium salts of sulfate esters, primarily estrone and 17α-estradiol. They contain 75% to 85% sodium estrone sulfate and 6% to 15% sodium equilin sulfate, with the total esterified estrogen content being 90% to 110% of the labeled amount; the combined estrone and equilin sulfate content accounts for at least 90% of the mixture. Esterified estrogens are primarily FDA-approved for managing moderate and severe vasomotor symptoms associated with menopause and moderate /severe vulvovaginal atrophy due to menopause as part of menopausal hormone therapy (MHT). Other indications include female hypogonadism, female castration, primary ovarian failure, and palliative treatment for breast cancer and advanced prostatic carcinoma, though these uses are less relevant to MHT.
Oral conjugated estrogens (CEEs): Conjugated estrogens are FDA-approved for moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause. As noted above, topical products are preferred for vaginal atrophy. Conjugated estrogens are also indicated for primary ovarian failure and palliative therapy of breast cancer. Conjugated estrogens are approved for preventing postmenopausal osteoporosis but should only be considered for women at significant risk, with non-estrogen therapies carefully evaluated.
Oral conjugated estrogens (CEEs) and bazedoxifene: The combination of conjugated estrogens and bazedoxifene is indicated for moderate or severe vasomotor symptoms associated with menopause and the prevention of postmenopausal osteoporosis.
[4] The bazedoxifene component helps reduce the risk of endometrial hyperplasia associated with the conjugated estrogens. Treatment should be used for the shortest duration consistent with treatment goals, with periodic re-evaluation to determine ongoing needs. For osteoporosis prevention, therapy should be considered only for women at significant risk and after careful consideration of non-estrogen options.
Depot estradiol cypionate: Estradiol cypionate injection is indicated for moderate or severe vasomotor symptoms associated with menopause and hypoestrogenism due to hypogonadism.
Depot estradiol valerate: Estradiol valerate injection is indicated for moderate or severe vasomotor symptoms and vulvovaginal atrophy associated with menopause, hypoestrogenism due to hypogonadism, primary ovarian failure, castration, and advanced androgen-dependent prostate carcinoma (for palliation). Topical vaginal products should be considered for vulvovaginal atrophy.
[5]
Estradiol patches: The primary difference between these estrogen transdermal systems lies in their delivery methods and patch frequencies. For vulvovaginal atrophy, topical vaginal products should be considered first. Transdermal estradiol is also indicated for postmenopausal osteoporosis. When prescribing solely for osteoporosis prevention, non-estrogen medications should be considered first, and estrogen therapy should be reserved for women at significant risk of osteoporosis. Some transdermal systems are approved for hypoestrogenism due to hypogonadism, primary ovarian failure, and the prevention of postmenopausal osteoporosis.
Estrogen-progestin patches: Transdermal estradiol plus levonorgestrel is indicated for moderate to severe vasomotor symptoms in menopause and the prevention of postmenopausal osteoporosis. The estradiol transdermal system combined with norethindrone acetate is a transdermal combination formulation indicated for the moderate or severe vasomotor symptoms associated with menopause and postmenopausal osteoporosis prevention in women with a uterus. A progesterone component is included to prevent the risk of endometrial hyperplasia, which can occur with unopposed estrogen therapy in women with a uterus.
Topical estradiol gel: Topical estradiol gel is approved for moderate to severe vasomotor symptoms due to menopause.
[6] Some formulations are also available as metered-dose pumps. Some formulations are also approved for reducing symptoms of vulvovaginal atrophy.
Topical estradiol spray: Estradiol spray is approved for moderate to severe vasomotor symptoms due to menopause.
[7]
Vaginal estradiol cream: Estradiol vaginal cream is indicated for moderate to severe vulvovaginal atrophy symptoms due to menopause.
[8] Conjugated estrogens vaginal cream, a mixture of estrogens, is indicated for atrophic vaginitis, kraurosis vulvae (lichen sclerosis), and moderate or severe dyspareunia associated with vulvovaginal atrophy due to menopause.
[9]
Vaginal estradiol ring: The estradiol vaginal ring is indicated for moderate/severe vulvovaginal atrophy due to menopause.
[10]
Vaginal tablet: The estradiol vaginal tablet is indicated for atrophic vaginitis due to menopause.
[11] An estradiol vaginal insert is indicated for treating moderate to severe dyspareunia secondary to vulvovaginal atrophy in women experiencing menopause.
[12][13]
Selective Estrogen Receptor Modulators: In postmenopausal women with osteoporosis, an elevated risk of fractures, and other characteristics listed below, the Endocrine Society guidelines recommend raloxifene or bazedoxifene to reduce the risk of vertebral fractures.
[14]
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Mechanism of Action
Estrogen therapy is primarily used to treat menopausal symptoms. Although estrogen is prescribed less often as a preventative therapy, it is still routinely administered to treat menopausal symptoms locally. Typically, drugs administered vaginally are primarily used for their local effects, but they can also have systemic effects. Estrogen is a steroid hormone that plays a central role in the reproductive system by altering the transcription of genes in specific organs and tissues, primarily the uterus and vagina. These genes, known as nuclear transcription factors, are altered once estrogen binds to their associated receptors. Once activated by estrogen, these nuclear transcription factors can bind to promoter regions in sequences of specific genes and are, therefore, able to regulate these genes.
[15] The augmentation or prevention of the transcription of these genes allows for the development, regulation, and maintenance of the uterus and vagina.
One important function of estrogen is its influence on the acidity level in the vaginal canal. The pH of the vaginal lumen in the years preceding menopause typically ranges between 4.5 and 6.0, as it varies relative to the menstrual cycle. Estrogen is responsible for decreasing the pH of the vaginal lumen by acting on the vaginal-ectocervical epithelial cells to increase proton secretion.
[16] During menopause, a decrease in estrogen levels causes an alkalinization of the vaginal canal, which reaches a pH of 6.5 to 7.0. A pH of above 6.5 correlates with an increased risk of vaginal infections, urinary tract infections, dryness, pruritus, and dyspareunia, all of which contribute to the symptoms of menopause.
[17] Furthermore, alkalinization of the vaginal lumen has associations with the tendency to form tumors within the cervix. Symptoms of menopause, such as hot flashes, mood swings, and sleep disturbances, are primarily due to reduced estrogen levels, which disrupt the body's temperature regulation and affect neurotransmitter activity. This hormonal change also leads to alterations in the sympathetic nervous system, causing vasomotor symptoms like hot flashes, while decreasing estrogen can contribute to mood and cognitive changes.
[18][19]
Pharmacokinetics
Absorption: As noted above, estrogen is administered through various formulations, such as oral or transdermal. Serum estradiol levels differ by formulation, even when similar doses of estrogen are used. Oral estrogens undergo first-pass metabolism in the liver, which can alter their bioavailability compared to transdermal formulations that bypass the liver initially. This leads to differing pharmacokinetic profiles.
[20]
Distribution: Estrogen is widely distributed, including target tissues such as the breast, endometrium, and bone. Estrogens are bound to sex hormone-binding globulin (SHBG) and albumin.
Metabolism: Exogenous estrogens are metabolized in the liver through enzymatic processes similar to those of endogenous estrogens. Estradiol is reversibly converted to estrone, and both estradiol and estrone can undergo further conversion to estriol, the principal urinary metabolite. Additionally, estrogens undergo enterohepatic recirculation, which involves hepatic sulfate and glucuronide conjugation, biliary excretion of conjugates into the intestines, hydrolysis in the gut, and reabsorption. In postmenopausal women, a significant proportion of circulating estrogens exists as estrone sulfate, which serves as a reservoir for the biosynthesis of more active estrogens. Estrogens are metabolized into inactive estrogenic metabolites, excreted via urine or feces. The initial step in estrogen metabolism involves hydroxylation, facilitated by cytochrome P450 enzymes, primarily in the liver. A major metabolite of estradiol, 2-hydroxy estradiol, is predominantly formed by CYP3A4 and CYP1A2 in the liver and CYP1A1 in extrahepatic tissues. However, CYP1B1, concentrated in estrogen-sensitive tissues such as the breast, ovary, and uterus, catalyzes the 4-hydroxylation of estradiol.
[21]
Elimination: Estrogens are primarily excreted in the urine. However, serum estradiol concentrations may not fully correlate with tissue-specific estrogenic activity due to the complex interactions between estrogens, their receptors, and downstream effects on target tissues. The various estrogen formulations, such as conjugated estrogens and estradiol, have different pharmacokinetic profiles. These findings emphasize the need to consider the pharmacokinetic properties of estrogen therapies in clinical practice. The pharmacokinetics of oral estrogens can vary between younger and older postmenopausal women due to age-related declines in muscle mass, liver and kidney function, and changes in body composition.
[22]
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Administration
Available Dosage Forms and Strengths
Estrogen therapy can be subdivided into 4 common forms of application: oral estrogen, transdermal estrogen, topical estrogen creams, and estrogen suppositories. Examples of oral estrogen include esterified estrogens, conjugated equine estrogens, ethinyl estradiol, and 17β-estradiol. The non-oral estrogen therapy is produced in the form of 17β-estradiol. Oral and transdermal estrogen are both equally equipped to provide menopausal symptom relief while sparing the bone. While many women would prefer the oral route, it requires a higher dose as its bioavailability is due to the first-pass metabolism in the liver.
[23]
Adult Dosing
The form of administration and dose varies with estrogen therapy and depends on the specific symptoms the treatment is targeting, as well as the anatomy of the patient being treated. Combined estrogen-progestin therapy for patients with an intact uterus should also be taken into consideration, as these patients need a progestin hormone to prevent endometrial hyperplasia associated with the administration of unopposed estrogen. Those who have undergone a hysterectomy can safely use unopposed estrogen to treat menopausal symptoms. Vasomotor symptoms are best controlled with systemic estrogen therapy. Conversely, symptoms involving the vaginal lumen, such as dyspareunia, vaginal itching, and vaginal dryness, are better controlled with local estrogen therapy. Estrogen therapy is typically administered orally or transdermally.
Estradiol patches are available in doses of 0.025 mg to 0.1 mg daily, and options involving weekly or twice-weekly administration are available. Oral estradiol is available in doses of 0.5 mg, 1 mg, and 2 mg, while esterified estrogens come in 0.3 mg, 0.625 mg, and 1.25 mg. Conjugated equine estrogens (CEEs) are available in doses ranging from 0.3 mg to 1.25 mg. Vaginal formulations target genitourinary atrophy; these include estradiol tablets (10 μg per tablet), vaginal cream (0.1 mg per gram), and the vaginal ring (0.05 mg or 0.1 mg per day over 3 months).
Estradiol cypionate and valerate are available in depot intramuscular injection. For topical application, estradiol gels provide 0.75 mg per pump, while estradiol solutions offer 0.52 mg per pump. Combination therapies offer varying dosages, such as those with estradiol and norethindrone acetate or drospirenone. Estrogen-progestin patches offer doses from 0.05 mg estradiol to 0.25 mg norethindrone.
Specific Patient Populations
Hepatic impairment: Systemic estrogen therapy is contraindicated for patients with hepatic impairment.
[24]
Renal impairment: Estrogen therapy can be considered for women with chronic kidney disease, but the choice of treatment should depend on the individual's preferences and cardiovascular health. The dose of hormonal and non-hormonal therapies must be adjusted based on the patient's kidney function, specifically creatinine clearance.
[25]
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Adverse Effects
There are several adverse effects of estrogen therapy that manifest in different ways depending on the route of administration and whether that route has local or systemic effects. A study exhibiting the adverse outcomes of hormone replacement therapy showed that unopposed estrogen correlates with an increased risk of endometrial and breast cancer. A large prospective study demonstrated a positive relationship between the estradiol form of estrogen and increased breast cancer risk. This study concluded that the relative risk was 1.7 (95% CI, 1.1 to 2.7) for women who used estrogen over 9 years and 1.8 (95% CI, 0.7 to 4.6) for those who used estradiol for more than 6 years. Another study showed a correlation between estrogen therapy and the risk of stroke, but that has yet to be confirmed.
[26]
Hormone replacement therapy, such as estrogen therapy, has also been associated with an increased risk of developing venous and pulmonary thromboembolism.
[27] Patients taking estrogen therapy for hormone replacement purposes should be thoroughly evaluated and considered on an individual basis to assess whether the benefits of estrogen therapy outweigh the risks. Additionally, the most common adverse effects experienced by women taking estrogen alone include breast tenderness, bloating, nausea, headaches, leg cramping, and vaginal or "breakthrough" bleeding.
