Continuing Education Activity

Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for developing female sexual characteristics. Estrogen or estradiol is the most common form of estrogen hormone for FDA-approved treatment as hormone replacement therapy (HRT) in managing symptoms associated with menopause. Furthermore, this activity will highlight the mechanism of action, adverse event profile, off-label uses, administration and dosing, monitoring, and relevant interactions pertinent for interprofessional team members.

Objectives:

• Identify the mechanism of action of estrogen.
• Describe contraindications to estrogen use.
• Describe estrogen toxicity.
• Outline the working relationships among interprofessional healthcare providers to promote the safe use of estrogen and to promote medication adherence.

Indications

Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for developing female sexual characteristics. Estrogen is often referred to as estrone, estradiol, and estriol. Of the previously mentioned forms of estrogen, estradiol is the most common form of estrogen hormone for hormone replacement therapy (HRT) in the treatment of symptoms of menopause. Estrogen for hormone replacement therapy has been heavily researched in medicine and remains a controversial topic. According to early studies, estrogen as hormone replacement therapy for postmenopausal women showed promising benefits of decreased risk of osteoporosis, coronary arterial disease, and mortality.[1] Later studies conducted by the Women's Health Initiative concluded that risk was greater than the benefit of hormone replacement therapy in postmenopausal women.

The Women's Health Initiative ended clinical studies prematurely because participants in the study developed an increased risk of breast cancer and coronary artery disease.[2] Newer studies contradict the finding of the Women's Health Initiative, with evidence of improved quality of life and reduced risk of coronary artery disease and osteoporosis in women when women start estrogen hormone replacement therapy at the onset of menopause.[3] The FDA has approved estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use, designed to increase absorption and effectiveness by altering the estrogen chemical structure for topical or oral administration. Synthetic steroid estrogens include ethinyl estradiol, estradiol valerate, estropipate, conjugate esterified estrogen, and quinestrol. Ethinyl estradiol is a commonly used synthetic estrogen to prevent pregnancy as a component of the oral contraceptive pill approved by the FDA.[4] Some nonsteroidal synthetic estrogens include dienestrol, diethylstilbestrol, benzestrol, methestrol, and hexestrol.

Clinically, the use of estrogen includes the following FDA-approved indications:

• Primary ovarian insufficiency
• Female hypogonadism
• Symptoms associated with menopause, including vulvovaginal atrophy, dyspareunia, hot flashes and night sweats, and prevention of osteoporosis 
• Oral contraceptive pill (OCP) to prevent pregnancy
• Moderate acne vulgaris 
• Prostate cancer with advanced forms of metastasis

Estrogen/synthetic estrogen has the following non-FDA-approved indication for polycystic ovarian syndrome to relieve symptoms of hyperandrogenism and amenorrhea.[5]

Mechanism of Action

Estrogen enters the systemic circulation as a free hormone or protein-bound, either to sex hormone-binding globulin (SHBG) or albumin. Non-protein-bound estrogen has the property to diffuse into cells freely with no regulation. Cellular physiological response to estrogen begins in the cell cytoplasm with estrogen binding to either alpha-estrogen receptor or beta-estrogen receptor. The activated estrogen-estrogen receptor complex then crosses into the nucleus of cells to induce DNA transcription by binding to nucleotide sequences known as estrogen response elements (ERE) to enact a physiological response. Estrogen hormone levels in the body are regulated by the negative feedback effect of estrogen on the hypothalamus and pituitary gland. An example of negative feedback can be observed during the menstrual cycle. Estrogen metabolic activity primarily occurs within the liver hepatocytes CYP3A4, and it is excreted from the body in the urine.[6][7][8]

The effects of estrogen on various systems of the body are described below:

• Breast: Estrogen is responsible for developing mammary gland tissue and parenchymal and stromal changes in breast tissue at puberty in females. Estrogen is also responsible for the development of mammary ducts during puberty and pregnancy, functions to secrete breast milk in postpartum lactation.
• Uterus: In the uterus, estrogen helps proliferate endometrial cells in the follicular phase of the menstrual cycle, thickening the endometrial lining in preparation for pregnancy.
• Contraception: Ethinyl estradiol, an ingredient of OCPs, functions to suppress the hypothalamus release of gonadotropin-releasing hormone (GnRH) and pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in preventing ovulation during the menstrual cycle.
• Vagina: Estrogen supports the proliferation of epithelial mucosa cells of the vagina and the vulva. In the absence of estrogen, the vaginal and vulvar mucosal epithelium becomes thin and presents with symptoms of dryness known as vulvovaginal atrophy.[9]
• Bone: During puberty, estrogen aids in the development of long bones and the fusion of the epiphyseal growth plates.[10] Estrogen protects bones by inactivating osteoclast activity, preventing osteoporosis in both estrogen-deficient and postmenopausal women.[11]
• Cardiovascular: Estrogen affects plasma lipids by increasing high-density lipoproteins (HDL) and triglyceride levels while decreasing low-density lipoproteins (LDL) and total plasma cholesterol and reducing the risk of coronary artery disease with early use in postmenopausal women.[12]

Administration

Estrogen hormone therapy may be prescribed in the following combinations as either estrogen-only medication or estrogen and hormone combination medication to treat symptoms of menopause, prevention of osteoporosis, prevention of pregnancy, hypoestrogenism, and metastatic breast and advanced prostate cancers.

Available Estrogen Preparations

Oral

• Estrogen: Conjugated may be prescribed in the dosage of 0.3 mg, 0.625 mg, 0.9 mg, and 1.25 mg tablets
• Estradiol may be prescribed in the dosage of 0.5 mg, 1 mg, and 2 mg tablets
• Norethindrone/ethinyl estradiol 1.5 mg/30 mcg tablets for oral contraception

Vaginal Ring

• Combination estrogen-etonogestrel/ethinyl estradiol hormone vaginal ring for contraception: 0.12 mg/0.015 mg per day.  
• Estradiol only vaginal ring for vulvovaginal atrophy: 7.5 mcg per day

Intramuscular Injection

• Estradiol valerate administered as an intramuscular injection in the dosage of 10 mg per mL, 20 mg per mL, and 40 mg per mL for vasomotor symptoms of menopause, vulvovaginal atrophy,  and hypoestrogenism. 
• Estradiol cypionate is administered as an intramuscular injection in the dosage of 5 mg per mL to treat moderate-to-severe symptoms of menopause.
• Recommendations for IM or SC palliative treatment for advanced prostate cancer depend on the precise formulation used and whether it is accompanied by concomitant oral therapy.

Transdermal

Available as a topical cream, topical spray, vaginal cream, vaginal tablet insert, and transdermal patch

• Estradiol topical gel (0.006%): 0.52 mg per pump
• Estradiol topical spray applied to the inner surface of the forearm: 1.53 mg per actuation.
• Estradiol hemihydrate tablet for vaginal insert may be prescribed at the following dosage: 10 mcg, 25 mcg tablet.
• Estrogen, conjugated vaginal cream: 0.625 mg per gram applied intravaginally.
• Estradiol transdermal patches may be prescribed at the following dosages: 0.025 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day.

Adverse Effects

Natural and synthetic estrogen may cause the following common adverse effects: breast tenderness, nausea, vomiting, bloating, stomach cramps, headaches, weight gain, hyperpigmentation of the skin, hair loss, vaginal itching, abnormal uterine bleeding, also known as breakthrough bleeding, and anaphylaxis.

Weight gain may be a reported adverse effect of the oral contraceptive pill (OCP) containing ethinyl estradiol, but studies conducted on short-term and long-term use of OCPs resulted in no weight gain association.[13][14]

More severe side effects of estrogen include hypertension, cerebrovascular accident, myocardial infarction, venous thromboembolism, pulmonary embolism, exacerbation of epilepsy, irritability, exacerbation of asthma, galactorrhea and nipple discharge, hypocalcemia, gallbladder disease, hepatic hemangioma and adenoma, pancreatitis, breast hypertrophy, endometrial hyperplasia, vaginitis, vulvovaginal candidiasis (intravaginal preparations), enlargement of uterine fibroids, and risk of cervical cancer and breast cancer.

Box Warnings

The use of estrogen without progestins increases the risk of endometrial cancer. The use of estrogen with and without progestins resulted in an increased risk of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years old) and an increased risk of invasive breast cancer in postmenopausal women (50 to 79 years old) with oral conjugated estrogens with medroxyprogesterone by studies established by the Women’s Health Initiative. The use of oral conjugated estrogens plus medroxyprogesterone acetate increased the risk of developing dementia in postmenopausal women older than 65 years of age, have been established by the Women’s Health Initiative Memory Study.[2][15]   

US Preventive Services Task Force (USPSTF) Score: D

Using estrogen-alone or combined estrogen and progestin to prevent a chronic condition in postmenopausal women with or without a uterus is not recommended by the US Preventive Services Task Force (USPSTF).[16]

Contraindications

The following are contraindications for the use of natural estrogen and synthetic estrogen derivatives:  

• Estrogen hormone receptor sensitive malignancies including breast cancer, ovarian cancer, and endometrial cancers
• Coronary arterial disease
• History of thromboembolism or thrombophlebitis
• History of hypercoagulable disease (Factor V Leiden syndrome, Protein C or Protein S deficiencies, and metastatic disease)
• History of ischemic stroke
• Migraine headaches
• Seizure disorder
• History of dementia or neurocognitive disorders
• Hypertension
• Uterine leiomyomas
• Endometriosis
• Urinary incontinence
• Hyperlipidemia
• Gallbladder disease
• Liver disease
• History of tobacco use
• Estradiol use in pregnancy is classified as pregnancy risk factor category X, and the use of esterified estrogens is contraindicated for use during pregnancy.

Monitoring

Before initiating estrogen therapy, clinicians should perform screening to assess the patient's risk of breast cancer, endometrial cancer, cardiovascular disease, including stroke, venous thrombosis, and myocardial infarction. Patients should also be screened for hypertension before starting estrogen therapy, and patients should continue to be monitored for the development of hypertension while taking estrogen. Routine women's wellness exams, including mammography and pap smear, should be continued during hormone replacement therapy with estrogen. Smoking cessation should be encouraged before the start and duration of OCPs since tobacco use increases the risk of venous thrombosis.[17]

The Endocrine Society recommends monitoring patients' improvement of postmenopausal symptoms while taking estrogen as hormone replacement therapy at the following intervals: first 1 to 3 months of therapy, then re-evaluated at 6 to 12 months of therapy annually after the first year.[18]

Toxicity

Although estrogen toxicity is not commonly described in the literature, numerous studies have shown that chronic exposure to estrogen poses a risk for the development of hormone-sensitive malignancy, increases the estrogen-containing risk of dementia and cardiovascular diseases in postmenopausal women treated with hormone replacement therapy. Symptoms of excess estrogen exposure include heavy menstruation, irritability and mood swings, headaches, sleep disturbances, breast cyst, endometriosis, fibroids, gallbladder disease, and thyroid disorders. Excess estrogen should also be considered in males who present with symptoms of infertility and gynecomastia.

High estrogen levels should raise suspicion for exposure to environmental estrogen, overexpression of the aromatase enzyme, and ectopic production of estrogens from hormone-producing malignant tissues. In addition to concerns for estrogen excess, it is crucial to consider drug-to-drug interactions that may induce or inhibit estrogen CYP3A4 metabolism in the liver.[7]

Enhancing Healthcare Team Outcomes

Using estrogen to treat postmenopausal symptoms and as a component of the oral contraceptive pill to prevent pregnancy remains widely available as FDA-approved therapy regardless of the known risk and benefits on women's health. For any patient of postmenopausal age, clinicians must ask patients about any history of estrogen hormone replacement therapy or use of estrogen oral contraceptive pills be included in the patient's medical history and physical exam. When clinicians first initiate estrogen therapies to patients, providers should evaluate patients for family history of breast cancer, endometrial cancer, ovarian cancer, history of cancer, and risk of newly developed malignancies sensitive to estrogen. 

Physicians and pharmacists should educate patients about the potential side effects and box warnings of estrogen use. Routine women wellness exams should also focus on the possible development of any malignancies or adverse effects of hormone replacement therapy given a positive history. The role of the pharmacist when counseling patients new to prescribed estrogen therapies should include educating and assessing the patient for proper use of estrogen medication therapies as they may be prescribed in many various preparations of oral, transdermal, vaginal insert, and topic vaginal creams for positive patient compliance and adherence to treatment. Nursing can also serve as a point of contact for medication-related questions, counseling regarding adverse effects, and coordinating activity among other interprofessional healthcare team members. This interprofessional approach will maximize therapeutic effectiveness and minimize possible adverse effects when using estrogen therapy. [Level 5]