Low Estrogen Symptoms – Causes, Symptoms

Low Estrogen Symptoms/Estrogen Hormone is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen or estradiol is the most common form of estrogen hormone for FDA-approved treatment as hormone replacement therapy (HRT) in the management of 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 members of the interprofessional team.

Types of Estrogen Hormone

There are different types of estrogen:

• Estrone – This type of estrogen is present in the body after menopause. It is a weaker form of estrogen and one that the body can convert to other forms of estrogen, as necessary.
• Estradiol – Both males and females produce estradiol, and it is the most common type of estrogen in females during their reproductive years. Too much estradiol may result in acne, loss of sex drive, osteoporosis, and depression. Very high levels can increase the risk of uterine and breast cancer. However, low levels can result in weight gain and cardiovascular disease.
• Estriol – levels of estriol rise during pregnancy, as it helps the uterus grow and prepares the body for delivery. Estriol levels peak just before birth.

Normal estrogen levels in women

According to Mayo Medical Laboratories, the following estrone and estradiol levels are considered normal for women:

Mechanism of Action

Estrogen enters the 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 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.[rx][rx][rx]

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.[rx]
• Bone – During puberty, estrogen aids in the development of long bones and fusion of the epiphyseal growth plates.[rx] Estrogen protects bones by inactivating osteoclast activity, preventing osteoporosis in both estrogen-deficient and postmenopausal women.[rx]
• 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 reduce the risk of coronary artery disease in early use in postmenopausal women.[rx]

Indications of Estrogen Hormone

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 in the following structures as either estrone, estradiol, and estriol.

• 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.[rx] 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.[rx] Newer studies contradict the finding of the Women’s Health Initiative, with evidence of the 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.[rx]
• 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.[rx] Some nonsteroidal synthetic estrogens include dienestrol, diethylstilbestrol, benzestrol, methestrol, and hexestrol.
• Conjugated estrogen therapy is indicated in the treatment of moderate to severe vasomotor symptoms due to menopause.
• Conjugated estrogen therapy is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
• Conjugated estrogen therapy is indicated in the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
• Conjugated estrogen therapy is indicated in the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
• Conjugated estrogen therapy is indicated in the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
• 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.

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.[rx]

Contraindications of Estrogen Hormone

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

Dosage of Estrogen Hormone

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

Estrogen Treatment: Pills

• What are they? Oral medication is the most common form of ERT. Examples are conjugated Estrogens (Premarin), estradiol (Estrace), and Estratab. Follow your doctor’s instructions for dosing. Most estrogen pills are taken once a day without food. Some have more complicated dosing schedules.
• Pros. Like other types of estrogen therapy, estrogen pills can reduce or resolve troublesome symptoms of menopause. They can also lower the risk of osteoporosis. While there are newer ways of getting ERT, oral estrogen medicines are the best-studied type of estrogen therapy.
• Cons. The risks of this type of estrogen therapy have been well-publicized. On its own, estrogen causes a slight increase in the risk of strokes, blood clots, and other problems. When combined with the hormone progestin, the risks of breast cancer and heart attack may rise as well. Oral estrogen-like any estrogen therapy — can also cause side effects. These include painful and swollen breasts, vaginal discharge, headache, and nausea.
  Because oral estrogen can be hard on the liver, people with liver damage should not take it. Instead, they should choose a different way of getting estrogen.

Side Effects of Estrogen Hormone

• 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.[rx][rx]
• 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.

Tell your doctor right away if you have any serious side effects, including mental, mood changes (such as depression, memory loss), breast lumps, unusual vaginal bleeding (such as spotting, breakthrough bleeding, prolonged, recurrent bleeding), increased or new vaginal irritation, itching, odor, discharge, severe stomach, abdominal pain, persistent nausea, vomiting, yellowing eyes, skin, dark urine, swelling hands, ankles, feet, increased thirst, urination.

Box Warnings

The 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. 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.[rx][rx]

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).[rx]

Drug Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug include: aromatase inhibitors (such as anastrozole, exemestane, letrozole), fulvestrant, ospemifene, raloxifene, tamoxifen, toremifene, tranexamic acid.

This medication may interfere with certain laboratory tests (including metyrapone test), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

Why is estrogen important?

Estrogen helps bring about the physical changes that turn a girl into a woman. This time of life is called puberty. These changes include:

• Growth of the breasts
• Growth of pubic and underarm hair
• Start of menstrual cycles

Estrogen helps control the menstrual cycle and is important for childbearing.

Estrogen also has other functions

• Keeps cholesterol in control
• Protects bone health for both women and men
• Affects your brain (including mood), bones, heart, skin, and other tissues

How does estrogen work?

The ovaries, which produce a woman’s eggs, are the main source of estrogen from your body. Your adrenal glands, located at the top of each kidney, make small amounts of this hormone, so does fat tissue. Estrogen moves through your blood and acts everywhere in your body.

What can go wrong with estrogen levels?

• For many reasons, your body can make too little or too much estrogen. Or, you can take in too much estrogen, such as through birth control pills or estrogen replacement therapy. You might want to keep track of your symptoms (changes you feel) by writing them down each day. Bring this symptom journal to your doctor.

Estrogen and your menstrual cycle

• Your estrogen levels change throughout the month. They are highest in the middle of your menstrual cycle and lowest during your period. Estrogen levels drop at menopause.
• How do you know what your estrogen level is? You will need to give a blood or urine sample to test your estrogen. Ask your doctor what your test results mean.

Low Estrogen

Women

The most common reason for low estrogen in women is menopause or surgical removal of the ovaries. Symptoms of low estrogen include:

• Menstrual periods that are less frequent or that stop
• Hot flashes (suddenly feeling very warm) and/or night sweats
• Trouble sleeping
• Dryness and thinning of the vagina
• Low sexual desire
• Mood swings
• Dry skin

Some women get menstrual migraines, a bad headache right before their menstrual period, because of the drop in estrogen.

Men – Low estrogen in men can cause excess belly fat and low sexual desire.

High Estrogen in Women

Excess estrogen can lead to these problems, among others:

• Weight gain, mainly in your waist, hips, and thighs
• Menstrual problems, such as light or heavy bleeding
• Worsening of premenstrual syndrome
• Fibrocystic breasts (non-cancerous breast lumps)
• Fibroids (noncancerous tumors) in the uterus
• Fatigue
• Loss of sex drive
• Feeling depressed or anxious
• bloating
• swelling and tenderness in your breasts
• fibrocystic lumps in your breasts
• decreased sex drive
• irregular menstrual periods
• increased symptoms of premenstrual syndrome (PMS)
• mood swings
• headaches
• anxiety and panic attacks
• weight gain
• hair loss
• cold hands or feet
• trouble sleeping
• sleepiness or fatigue
• memory problems

Men. High estrogen in men can cause

• Infertility – Estrogen is partly responsible for creating healthy sperm. When estrogen levels are high, sperm levels may fall and lead to fertility issues.
• Gynecomastia – Estrogen may stimulate breast tissue growth. Men with too much estrogen may develop gynecomastia, a condition which leads to larger breasts.
• Erectile dysfunction (ED) – Men with high levels of estrogen may have difficulty getting or maintaining an erection.
• Enlarged breasts (gynecomastia)
• Poor erections
• Infertility

Monitoring

Prior to the initiation of the use of estrogen, screening should be conduct towards the patient’s 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.[rx]

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.[rx]

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