Continuing Education Activity

Estrogen therapy is a form of hormone replacement therapy that is often used to manage and treat menopausal symptoms, especially vasomotor symptoms and urogenital atrophy, which is often associated with a significantly decreased quality of life. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of estrogen therapy.

Objectives:

• Identify the mechanism of action of estrogen therapy.

• Describe the possible adverse effects of estrogen therapy.

• Summarize the appropriate monitoring for patients using estrogen therapy.

• Explain interprofessional team strategies for improving care coordination and communication to advance estrogen therapy and improve outcomes.

Indications

Estrogen therapy (ET), a form of hormone replacement therapy (HRT), is a useful way of combating the uncomfortable symptoms that often accompany menopause.[1] Roughly 1.5 million women between the ages of 45 and 55 experience menopausal symptoms, often involving hot flashes, flushing, and night sweats, also known as vasomotor symptoms. Additional symptoms include irritability, mood and sleep disturbances, fatigue, decreased libido, dyspareunia, and atrophic vaginitis. The Women's Health Initiative trial has made the use of estrogen therapy obsolete to prevent 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, particularly in the non-systemic form, in women experiencing distressing symptoms. Without it, a third of women experience at least itching, irritation, dryness, and dyspareunia, leading to decreased 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 in assessing its benefits and uses. For example, the use of estrogen transdermally, in stark contrast to orally, has been linked to a lower risk of deep vein thrombosis, cholecystitis, osteoporosis, and stroke. Estrogen therapy has also proved beneficial in a patient with an increased risk of osteoporotic fractures with long-term use.

Mechanism of Action

The primary use of estrogen therapy lies in its treatment of menopausal symptoms. Although there is currently a reduction in estrogen therapy as a preventative treatment, it is still routinely used to treat menopausal symptoms locally. Typically, drugs administered vaginally are used mainly 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. The genes undergo alteration through the act of estrogen on certain receptors, known as nuclear transcription factors. Once bound by estrogen, these nuclear transcription factors are then able to bind to promoter regions in sequences of specific genes and are therefore able to regulate these genes.[3] Once these genes get transcribed, this allows for the development, regulation, and maintenance of the uterus and vagina.

One important function of estrogen is its influence on the acid pH 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.[4] Once a woman experiences menopause, there is a decrease in estrogen, causing an alkalinization of the vaginal canal to about 6.5 to 7.0. A pH of above 6.5 correlates with an increased risk of vaginal infections, UTIs, dryness, pruritus, and dyspareunia, all of which contribute to the symptoms of menopause. Furthermore, alkalinization of the vaginal lumen has associations with the tendency of forming tumors within the cervix.

Administration

The form of administration varies with estrogen therapy and depends on the specific symptoms the treatment is targeting. Essentially, certain symptoms, such as the vasomotor symptoms experienced during menopause, would best be controlled with estrogen therapy that acts systemically. Conversely, symptoms involving the vaginal lumen, such as dyspareunia, vaginal itching, and vaginal dryness, experience more control with locally acting estrogen therapy. Typically, women with an intact uterus receive combination estrogen and progesterone therapy. Women who have had hysterectomies receive estrogen alone. Usually, estrogen therapy divides into two main routes administered either orally or transdermally.

Estrogen therapy further subdivides specifically into four common forms of application: oral estrogen in the form of pills, transdermal estrogen, estrogen creams, and estrogen suppositories. Examples of oral estrogen include esterified estrogens, conjugated equine estrogens, ethinyl estradiol, 17 beta-estradiol. The non-oral estrogen therapy is produced in the form of 17 beta-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.[5]

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 exhibited a positive relationship between estrogen, used in the form of estradiol, 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 for more than nine years and 1.8 (95% CI 0.7 to 4.6) for those who used estradiol for more than six years. Another study showed a correlation between estrogen therapy and the risk of stroke, but that has yet to be confirmed.[6]

Hormone replacement therapy, such as estrogen therapy, has also been associated with an increased risk of developing venous and pulmonary thromboembolism.[7] 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.

Contraindications

Hormone replacement therapy, which includes estrogen therapy taken either orally or transdermally, has several contraindications that correlate with the adverse effects and relative toxicity of estrogen-based formulations. These include patients who have a known or suspected history of any form of breast or uterine cancer, a history of deep vein thrombosis or pulmonary embolism, a history of stroke or myocardial infarction, or a history of blood clotting disorders.[7] Those patients who have a history of stroke, particularly ischemic stroke events, might benefit from estrogen therapy as the current literature on the contraindication in stroke patients is controversial.[5] These contraindications do not apply to estrogen taken transvaginally, as in the form of creams or suppositories, as the serum level of estrogen via this route is too low to cause any effect.

Monitoring

The monitoring and close follow-up of patients on estrogen therapy is not as strict as it would be with patients on warfarin, as symptom relief and absence of adverse effects are enough to determine the need for intervention or adjustment. Many patients on estrogen therapy undergo re-evaluation after several months for possible dose adjustments based on the response to the treatment and relief of symptoms. Depending on the health status and co-morbid conditions, an annual exam is subsequently part of the continued care to re-assess the risks and benefits individualized to each woman. The yearly exam includes several history taking and physical examination techniques used to evaluate whether adverse events or toxicity is developing, including breast and pelvic exam, review of any health concerns, and reassessment of symptoms.

Toxicity

The toxicity of estrogen is dose-dependent. If a patient takes too much estrogen, the potential toxicity lies in the organs it affects. In high doses, estrogen therapy can potentially cause severe effects, including excessive vaginal bleeding, fluid retention, and mental status changes. In a study analyzing the effects of estrogen therapy in surgically-induced postmenopausal mice, the results suggested that estrogen taken in high doses is associated with harmful effects on the heart but negatively impacted renal function.[8]

Enhancing Healthcare Team Outcomes

Treating menopausal symptoms can often be challenging, as the symptoms tend to vary on an individual basis. Many women experience only local or systemic symptoms, while some experience a combination of both. The cause of menopause is typically the same for many women, regardless of whether the symptoms are local or systemic. Women, specifically those experiencing signs of urogenital atrophy, also tend to feel embarrassed to report these symptoms or think that the local or topical therapy will carry the same risk as does the systemic treatment of menopausal symptoms, known as menopausal hormone therapy (MHT). Around 50% of women will experience symptoms of urogenital atrophy, which include vaginal dryness, itching, infections of the urinary tract, urinary incontinence, and dyspareunia. Unfortunately, only 25% of them will seek options for treatment and avoid treatment altogether.[5] 

Urogenital atrophy, using treatment with topical forms of estrogen, and systemic menopausal symptoms, treated with estrogen therapy taking orally, have vastly different risks and benefits. MHT, which includes estrogen and progesterone, used to manage the systemic vasomotor symptoms of menopause, correlates with an elevated risk of breast cancer after 3 to 5 years of continuous use. Local estrogen creams, as opposed to systemic MHT, promotes vaginal maturation and thickening.[5] Some of the types of estrogen creams have the potential to be absorbed when applied to a thinned vaginal canal, but as it thickens with treatment, absorption reduces significantly, which then reduces the potential for systemic effects of the locally applied estrogen. Since only half of women experiencing urogenital atrophy actually seek treatment, an initiative by primary healthcare providers, including physicians, mid-level practitioners, and nurse practitioners involved in the patient's care, should take place to clearly outline the difference of the risk and benefits of topical estrogen therapy and systemic MHT. This information will provide women with a clear outline that will allow them to make the best decision for treating the local menopausal symptoms that often lead to a significantly decreased quality of life.

Estrogen therapy requires the efforts of an interprofessional team that includes physicians, pharmacists, and specialty-trained nurses to optimize patient treatment and outcomes. [Level 5]