Estrogen


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Benjamin Delgado


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Updated:
5/16/2019 1:54:45 PM

Indications

Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen is often referred to the following structures as either 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. The use of 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 of 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 approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of 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 for the relief of symptoms of hyperandrogenism and amenorrhea.[5]

Mechanism of Action

Estrogen enters systemic circulation as a free hormone or protein-bound, either as sex hormone-binding globulin (SHBG) or albumin. Non-protein-bound estrogen has the property to diffuse into cells freely with no regulation. The initiation of a cellular physiological response to estrogen begins in the cell cytoplasm with the binding of estrogen to either alpha-estrogen receptor or beta-estrogen receptor. The activated estrogen-estrogen receptor complex then crosses into the nucleus of cells to induce transcription of DNA 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 takes place within the liver hepatocytes CYP3A4 and 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 the development of 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 during pregnancy, functions to secrete breast milk in postpartum lactation.
  • Uterus: In the uterus, estrogen helps to 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 aides in the development of long bones and 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 effects plasma lipids by increasing high-density lipoproteins (HDL) and triglyceride levels while decreasing low-density lipoproteins (LDL) and total plasma cholesterol and reduce the risk of coronary artery disease in 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 advance 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. Recommendations for advanced prostate cancer palliative treatment is more than 30-mg intramuscular injection.
  • Estradiol cypionate administered as an intramuscular injection in the dosage of 5 mg per mL for treatment of moderate-to-severe symptoms of menopause.

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 patch may be prescribed at the following dosage: 0.025 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day.

Adverse Effects

Natural estrogen 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

Use of estrogen without progestins increased 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. 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 use 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 are contraindicated for use during pregnancy

Monitoring

Prior to the initiation of the use of estrogen, screening should be conduct towards the patients risk of breast cancer, endometrial cancer, the risk of cardiovascular disease including stroke, venous thrombosis, and myocardial infarction. Patients should also be screened for hypertension before starting estrogen therapy, and patients should be continued 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 the use of hormone replacement therapy with estrogen. Smoking cessation should be encouraged before the start and duration of use of OCPs due to tobacco use having an increased 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 the start of therapy, then re-evaluated at 6 to 12 months of therapy, then annually after the first year.[18]

Toxicity

Although estrogen toxicity is not largely described in the literature, numerous studies have shown that chronic exposure to estrogen poses a risk for the development of hormone-sensitive malignancy, increase the estrogen-containing risk of dementia, and increases the risk of 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 levels of estrogen 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 important to consider drug-to-drug interactions that may either 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 on the market as FDA-approved therapy regardless of the known risk and benefits on women's health. For any patient of postmenopausal age, it is essential that clinicians ask patients about any history of estrogen hormone replacement therapy or use of estrogen oral contraceptive pills be included in patient's medical history and physical exam. When physicians 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 pharmacist should invest time to educate patients about the potential side effects and box warnings of estrogen use. Routine women wellness exams should also be focused on the 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 therapy.


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Estrogen - Questions

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Which of the following is associated with exogenous estrogens?



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The incidence of what cancer is increased with unopposed estrogen?



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In reference to hemostasis mechanisms, what effect does estrogen exerts on coagulation?



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Estrogen - References

References

Lobo RA,Pickar JH,Stevenson JC,Mack WJ,Hodis HN, Back to the future: Hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis. 2016 Nov;     [PubMed]
Rossouw JE,Anderson GL,Prentice RL,LaCroix AZ,Kooperberg C,Stefanick ML,Jackson RD,Beresford SA,Howard BV,Johnson KC,Kotchen JM,Ockene J, Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;     [PubMed]
Lobo RA, Hormone-replacement therapy: current thinking. Nature reviews. Endocrinology. 2017 Apr;     [PubMed]
Archer DF,Nakajima ST,Sawyer AT,Wentworth J,Trupin S,Koltun WD,Gilbert RD,Ellman H, Norethindrone acetate 1.0 milligram and ethinyl estradiol 10 micrograms as an ultra low-dose oral contraceptive. Obstetrics and gynecology. 2013 Sep;     [PubMed]
Bednarska S,Siejka A, The pathogenesis and treatment of polycystic ovary syndrome: What's new? Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2017 Mar-Apr;     [PubMed]
Sier JH,Thumser AE,Plant NJ, Linking physiologically-based pharmacokinetic and genome-scale metabolic networks to understand estradiol biology. BMC systems biology. 2017 Dec 15;     [PubMed]
Kumar A,Banerjee A,Singh D,Thakur G,Kasarpalkar N,Gavali S,Gadkar S,Madan T,Mahale SD,Balasinor NH,Sachdeva G, Estradiol: A Steroid with Multiple Facets. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2018 May;     [PubMed]
Mac Bride MB,Rhodes DJ,Shuster LT, Vulvovaginal atrophy. Mayo Clinic proceedings. 2010 Jan;     [PubMed]
Weise M,De-Levi S,Barnes KM,Gafni RI,Abad V,Baron J, Effects of estrogen on growth plate senescence and epiphyseal fusion. Proceedings of the National Academy of Sciences of the United States of America. 2001 Jun 5;     [PubMed]
Klein-Nulend J,van Oers RF,Bakker AD,Bacabac RG, Bone cell mechanosensitivity, estrogen deficiency, and osteoporosis. Journal of biomechanics. 2015 Mar 18;     [PubMed]
Hong MK,Romm PA,Reagan K,Green CE,Rackley CE, Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women. The American journal of cardiology. 1992 Jan 15;     [PubMed]
Mayeda ER,Torgal AH,Westhoff CL, Weight and body composition changes during oral contraceptive use in obese and normal weight women. Journal of women's health (2002). 2014 Jan;     [PubMed]
Lindh I,Ellström AA,Milsom I, The long-term influence of combined oral contraceptives on body weight. Human reproduction (Oxford, England). 2011 Jul;     [PubMed]
Shumaker SA,Legault C,Rapp SR,Thal L,Wallace RB,Ockene JK,Hendrix SL,Jones BN 3rd,Assaf AR,Jackson RD,Kotchen JM,Wassertheil-Smoller S,Wactawski-Wende J, Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;     [PubMed]
Grossman DC,Curry SJ,Owens DK,Barry MJ,Davidson KW,Doubeni CA,Epling JW Jr,Kemper AR,Krist AH,Kurth AE,Landefeld CS,Mangione CM,Phipps MG,Silverstein M,Simon MA,Tseng CW, Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: US Preventive Services Task Force Recommendation Statement. JAMA. 2017 Dec 12;     [PubMed]
Lefèvre D,Mouroziès X,Fontan R,Hammoudi S,Becade P,Mazères F,Bastide G, [Vascular thrombosis and oral contraceptives]. Phlebologie. 1987 Oct-Dec;     [PubMed]
Stuenkel CA,Davis SR,Gompel A,Lumsden MA,Murad MH,Pinkerton JV,Santen RJ, Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2015 Nov;     [PubMed]
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