Estrogen

Benjamin J. Delgado; Wilfredo Lopez-Ojeda.

Author Information and Affiliations

Last Update: June 26, 2023.

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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.
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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]
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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]
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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.
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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]
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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.
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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]
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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]
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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]
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Review Questions
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References
1.
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;254:282-290. [PubMed]
2.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg
C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson
KC, Kotchen JM, Ockene J., Writing Group for the Women's Health
Initiative Investigators. 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;288(3):321-33. [PubMed]
3.
Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev
Endocrinol. 2017 Apr;13(4):220-231. [PubMed]
4.
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. Obstet Gynecol. 2013 Sep;122(3):601-
7. [PubMed]
5.
Bednarska S, Siejka A. The pathogenesis and treatment of polycystic
ovary syndrome: What's new? Adv Clin Exp Med. 2017 Mar-
Apr;26(2):359-367. [PubMed]
6.
Sier JH, Thumser AE, Plant NJ. Linking physiologically-based
pharmacokinetic and genome-scale metabolic networks to
understand estradiol biology. BMC Syst Biol. 2017 Dec
15;11(1):141. [PMC free article] [PubMed]
7.
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. Horm Metab Res. 2018
May;50(5):359-374. [PubMed]
8.
Hamilton KJ, Hewitt SC, Arao Y, Korach KS. Estrogen Hormone
Biology. Curr Top Dev Biol. 2017;125:109-146. [PMC free article]
[PubMed]
9.
Mac Bride MB, Rhodes DJ, Shuster LT. Vulvovaginal
atrophy. Mayo Clin Proc. 2010 Jan;85(1):87-94. [PMC free article]
[PubMed]
10.
Weise M, De-Levi S, Barnes KM, Gafni RI, Abad V, Baron J.
Effects of estrogen on growth plate senescence and epiphyseal
fusion. Proc Natl Acad Sci U S A. 2001 Jun 05;98(12):6871-
6. [PMC free article] [PubMed]
11.
Klein-Nulend J, van Oers RF, Bakker AD, Bacabac RG. Bone cell
mechanosensitivity, estrogen deficiency, and osteoporosis. J
Biomech. 2015 Mar 18;48(5):855-65. [PubMed]
12.
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. Am J Cardiol. 1992 Jan 15;69(3):176-8. [PubMed]
13.
Mayeda ER, Torgal AH, Westhoff CL. Weight and body
composition changes during oral contraceptive use in obese and
normal weight women. J Womens Health (Larchmt). 2014
Jan;23(1):38-43. [PMC free article] [PubMed]
 14.
Lindh I, Ellström AA, Milsom I. The long-term influence of
combined oral contraceptives on body weight. Hum Reprod. 2011
Jul;26(7):1917-24. [PubMed]
15.
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene
JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM,
Wassertheil-Smoller S, Wactawski-Wende J., WHIMS Investigators.
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;289(20):2651-62. [PubMed]
16.
US Preventive Services Task Force. Grossman DC, Curry SJ, Owens
DK, Barry MJ, Davidson KW, Doubeni CA, Epling JW, 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;318(22):2224-2233. [PubMed]
17.
Lefèvre D, Mouroziès X, Fontan R, Hammoudi S, Becade P,
Mazères F, Bastide G. [Vascular thrombosis and oral
contraceptives]. Phlebologie. 1987 Oct-Dec;40(4):981-6. [PubMed]
18.
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. J
Clin Endocrinol Metab. 2015 Nov;100(11):3975-4011. [PubMed]
Disclosure: Benjamin Delgado declares no relevant financial relationships with
ineligible companies.

Disclosure: Wilfredo Lopez-Ojeda declares no relevant financial relationships

with ineligible companies.
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