Continuing Education Activity

Estradiol is a medication used to manage and treat postmenopausal symptoms and for women who have had hysterectomies. Estradiol is the most potent estrogen (E2) in the human body. Postmenopausal symptoms include, but are not limited to: vaginal dryness, itchiness, dysuria, and many more. This activity reviews the mechanism of action, risks, benefits, indications, contradictions, side effects, and other critical elements of estradiol therapy.

Objectives:

• Review the pathophysiology of estradiol.
• Summarize the administration of estradiol.
• Identify the contraindications of estradiol therapy.
• Explain the importance of care amongst the interprofessional team to enhance the quality of life in postmenopausal women.

Indications

Estradiol is a hormone made naturally in the human body by the ovaries. It is crucial in regulating the menstrual cycle, cardiovascular system, neurologic system, skeletal system, vascular system, and many more.[1] Estradiol is the most potent and abundant estrogen (E2) during a woman's reproductive years. There are four different kinds of estrogen: estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4).[2]

When women enter menopause, estrogen synthesis significantly decreases due to lower-functioning ovaries. The decrease in estrogen is the reason most women have postmenopausal symptoms. Postmenopausal symptoms include but are not limited to hot flashes, vaginal dryness, vaginal itchiness, dysuria, and dyspareunia. These symptoms can be very discomforting to patients and affect the quality of life, sleep, mood, interpersonal relationships, daily activities, and sexual function. When the ovaries no longer synthesize estradiol, it can then get synthesized by several extragonadal sites.[3] These sites include adipose tissue, bones, brain, and smooth muscle cells in vascular endothelium, as well as others. 

Before women enter menopause, estradiol protects women from cardiovascular disease due to increased regulation of cholesterol and triglyceride metabolism, thus decreasing the risk for atherosclerotic heart disease.[4] To combat these symptoms, estradiol can be taken supplementally to manage and treat postmenopausal symptoms and for women who have had hysterectomies, salpingo-oophorectomy, or unilateral salpingo-oophorectomy. Estrogen is also useful in female patients with hypoestrogenism due to castration, hypogonadism, or primary ovarian failure, such as Turner syndrome. 

The majority of studies find that postmenopausal symptoms experience significant improvement with the use of estradiol hormone replacement therapy (HRT). Also, research has shown that estradiol can decrease stress by reducing the release of cortisol in response to a physical stressor. Estradiol increases the amount of corticosteroid-binding globulin (CBG), thus reducing the free cortisol levels circulating in the body, responding to stress. Less cortisol can act on the body, including areas in the brain that are integral to the stress response.[5]

Estrogen formulations have also served as an off-label treatment option for male-to-female transgender patients. However, the levels of blood estrogen levels require close monitoring to avoid complications of the treatment. 

Estrogen has a significant role in bone health. Women in postmenopausal age develop osteoporosis due to decreased levels of estrogen. Estrogen-derived formulations such as raloxifene have received approval for osteoporosis prevention and treatment in a selected patient population. 

Mechanism of Action

Estrone is converted to estradiol in the granulosa cells of the ovary by the enzyme 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD).[2] The aromatization of testosterone synthesizes estradiol. Estradiol is a steroid hormone and, therefore, can easily cross the cell membrane. Estrone binds to its specific intracellular receptor and regulates DNA transcription for protein formation.[2] Estrone exerts its effects on the menstrual cycle, breasts, ovaries, brain, musculoskeletal system, cardiovascular system, and more. Estrone appears to affect the gene transcription of other genes that do not have estrogen-responsive elements.

Administration

Hormone replacement therapy (HRT) is normally used for a short period in post-menopausal women. The routes of admission can be transdermal (cream and patches), intramuscular, or oral. Estradiol therapy usually comes in two forms: as a vaginal cream or as a capsule. Studies have found that using estradiol vaginal cream twice a week has significantly reduced vaginal dryness and dyspareunia compared to placebo pills. However, there was no significant improvement between estradiol vaginal cream and placebo therapy in vaginal irritation, itchiness, and dysuria.[6]

There is still research underway to determine the efficacy of vaginal estradiol capsules. Capsules currently undergoing clinical trials hope to relieve post-menopausal symptoms with very little systemic estradiol exposure. The capsules should be less messy and more patient-friendly than creams and tablets.[7]

In one clinical trial, capsules improved vaginal dryness and dyspareunia. Also, capsules increased the percentage of superficial and intermediate cells in the vagina, thus improving vaginal physiology.

Sustained-release estradiol vaginal rings are becoming more popular in research. Rings can be effective for up to 90 days and can be easily inserted and removed by patients.[8] The ring may be beneficial to women who choose not to apply vaginal estrogen creams. 

Adverse Effects

Adverse effects are generally uncommon; however, there have been reports of the following: 

• Cardiovascular: edema, hypertension, thrombophlebitis, retinal thrombosis. 
• Central Nervous System: headache, depression, pain, dizziness, anxiety, migraine, nipple pain
• Respiratory: nasopharyngitis, flu-like symptoms, sinusitis, upper respiratory tract infection, headache, bronchitis, sinus congestion, pharyngitis, asthma exacerbation, cough 
• Dermatologic: skin rash, pruritus, erythema multiforme, erythema nodosum, urticaria
• Skeletal: arthralgia, weakness, back and neck pain, limb pain, myalgia, leg cramps
• Endocrine: weight gain or loss, hot flash, libido changes, hirsutism, menstrual changes, porphyria exacerbation, fluid retention, hypocalcemia, elevated triglycerides, galactorrhea
• Gastrointestinal: Abdominal pain, constipation, heartburn, flatulence, bloating, nausea, vomiting, diarrhea, pancreatitis, gastroenteritis, carbohydrate intolerance 
• Hypersensitivity: anaphylaxis, angioedema, hypersensitivity reactions
• Hepatic: Hepatic hemangioma exacerbation, jaundice
• Ophthalmic: conjunctivitis, steepening of the cornea, contact lens intolerance 
• Infections: fungal and other infections
• Otic: Otitis media 

The United States Food and Drug Administration (FDA) Boxed Warnings

• Women who take estrogen plus progestin therapy are at increased risk for breast cancer.
• Women with increased exposure to estrogen are at risk for endometrial cancer. Estrogen stimulates endometrial growth, which results in endometrial hyperplasia, which could result in endometrial cancer.
• Other risk factors associated with increased exposure to estrogen HRT are cerebrovascular events, coronary artery disease, and venous thromboembolism.[9] There have also been reports of ovarian cancer with estrogen use. 

Contraindications

Women who are at increased risk of breast cancer or endometrial cancer should not begin Estradiol therapy.

Overweight women with exposure to increased estradiol levels in their lifetime should not add supplemental estradiol to their post-menopause regimen.[10] Adipose tissue carries an increased level of estrogen. Therefore overweight women are at risk of increased exposure compared to average-weight and underweight women. 

Women who have angioedema or anaphylactic reaction to estradiol or its components, abnormal genital bleeding, blood clotting disorders such as deep venous thrombosis or pulmonary thromboembolism, cardiovascular disease (a stroke or myocardial infarction), protein C or S  or antithrombin deficiency, as well as thrombophilic disorders, or pregnancy, are contraindications to estradiol treatment. 

Estradiol HRT can increase a patient's risk of cardiovascular disease, DVT, and stroke and, therefore, is not a viable option in at-risk patients.  

Women at risk can consider other alternatives such as laser therapy, lubricants, dilators, and even physical therapy to strengthen pelvic floor muscles if patients complain of dyspareunia.[8]

Monitoring

There is not much monitoring for estradiol therapy for women who choose to use vaginal creams or capsules. However, women who choose to use the high-dose estradiol vaginal ring should understand the risks due to increased estradiol in systemic circulation. 

If a woman is at risk of developing endometrial cancer and chooses to undergo estradiol HRT, she should continually undergo endometrial monitoring. 

Levels of estrogen are monitored in transgender patients and maintained according to Endocrine Society guidelines. 

Toxicity

There are no published reports of estradiol toxicity in humans. However, one study measured estradiol toxicity in amphibians' embryos.[11] Research determined that estradiol toxicity occurred when the amount of estradiol severely outnumbered estradiol receptors; this was an incredibly high number that would be highly unlikely in a human population. Estradiol excess may lead to side effects and complications noted in the adverse effect section.

Enhancing Healthcare Team Outcomes

Educating women about the physiology behind post-menopausal symptoms is essential so that they can understand the changes that occur with decreased estrogen. Many women are embarrassed and shy to talk about this topic. Primary care clinicians and obstetricians-gynecologists should ask and encourage women to talk about their symptoms. Providers will better be able to offer advice, tips, and education, as indicated.

An interprofessional healthcare team approach is the optimal path to follow when initiating or considering initiating estradiol therapy. The family clinician and gynecologist should coordinate their efforts. A pharmacist should review the patient's medication record, verify that dosing is appropriate, and counsel the patient regarding potential adverse effects to report these to the prescriber should they present. Nursing must also assist the team by counseling the patient so they are aware of possible adverse events. They can also monitor the patient on follow-up visits and determine how effectively the patient responds to treatment. This interprofessional team paradigm optimizes treatment and avoids adverse events, thereby improving patient outcomes. [Level 5]