What is estrogen

Estrogens are a group of female hormones that are responsible for the development and function of reproductive organs and the formation of secondary sex characteristics in women. Estrogen also has other functions: keeps cholesterol in control, protects bone health for both women and men and affects your brain (including mood), bones, heart, skin, and other tissues.

Estrogen is produced by the ovaries, adrenal glands and the placenta during pregnancy ¹⁾ and to a lesser extent, by peripheral steroidogenic conversion by fat tissue and by the testes in men ²⁾. Women have about four times the amount of estrogens compared with men ³⁾. Follicle-stimulating hormone (FSH) stimulates the ovarian production of estrogens by the granulosa cells of the ovarian follicles and corpora lutea. Some estrogens are also produced in smaller amounts by other tissues such as the liver, pancreas, bone, adrenal glands, skin, brain, adipose tissue ⁴⁾ and the breasts ⁵⁾. These secondary sources of estrogens are especially important in postmenopausal women ⁶⁾. The pathway of estrogen biosynthesis in extragonadal tissues is different. These tissues are not able to synthesize C19 steroids, and therefore depend on C19 supplies from other tissues ⁷⁾ and the level of aromatase ⁸⁾.

In females, synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of weak androgenic activity which serves predominantly as a precursor for more potent androgens such as testosterone as well as estrogen. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted either immediately into estrone, or into testosterone and then estradiol in an additional step (see Figure 2). The conversion of androstenedione to testosterone is catalyzed by 17β-hydroxysteroid dehydrogenase, whereas the conversion of androstenedione and testosterone into estrone and estradiol, respectively is catalyzed by aromatase, enzymes which are both expressed in granulosa cells. In contrast, granulosa cells lack 17α-hydroxylase and 17,20-lyase, whereas theca cells express these enzymes and 17β-hydroxysteroid dehydrogenase but lack aromatase. Hence, both granulosa and theca cells are essential for the production of estrogen in the ovaries.

Estrogen, along with progesterone, they help regulate the menstrual cycle, are involved in the growth of breasts and the uterus, and help maintain a healthy pregnancy. Though estrogen is considered the main sex hormones for women, they are also found in men and play a role in bone metabolism and growth in both sexes. However, the regulation of human male reproduction is more complex and the role of estrogens is less clear compared to women ⁹⁾.

In humans, the three major endogenous estrogens are estrone (E1), estradiol (E2), and estriol (E3) ¹⁰⁾. Another type of estrogen called estetrol (E4) is produced only during pregnancy. Quantitatively, estrogens circulate at lower levels than androgens in both men and women ¹¹⁾. While estrogen levels are significantly lower in males compared to females, estrogens nevertheless also have important physiological roles in males ¹²⁾.

Estrone (E1) is the only estrogen your body makes after menopause (when menstrual periods stop). Estrone (E1) is directly converted from androstenedione (from the adrenal gland) or indirectly from other androgens. Estrone (E1) can also be produced by the ovaries and placenta, testicles, and adipose (fat) tissues. Estradiol (E2) and estrone (E1) can be converted into each other as needed. Estrone (E1) is the primary estrogen in men and in post-menopausal women.

Estradiol (E2) is the most common type in women of childbearing age. Estradiol (E2) is primarily produced in the ovaries in pre-menopausal women and in the testicles in men. Estradiol (E2) is converted from estrone (E1) in post-menopausal women. It is the most potent estrogen and the one that is present in the highest concentration in non-pregnant, pre-menopausal women. Estradiol (E2) levels vary depending on a woman’s age and reproductive status. They are a good marker of ovarian function.

Estriol (E3) is produced by the placenta, with concentrations rising throughout a woman’s pregnancy. Increasing levels are an indication of the health of the pregnancy and developing baby. Estriol (E3) is part of the second trimester maternal serum screen, a test performed to evaluate fetal risk due to certain chromosomal abnormalities. Very low levels of estriol (E3) are present in non-pregnant women or men.

Estetrol (E4) is a weak estrogen steroid hormone which is found in detectable levels only during pregnancy ¹³⁾. Estetrol (E4) is produced exclusively by the fetal liver ¹⁴⁾. Estetrol (E4) is closely related to estriol (E3), which is also a weak estrogen that is found in high quantities only during pregnancy Along with estradiol (E2), estrone (E1), and estriol (E3), estetrol (E4) is a major estrogen in the body, although only during pregnancy.

In addition to their role as natural hormones, estrogens are used as medications, for instance in menopausal hormone therapy and hormonal birth control.

Figure 1. Estrogen chemical structures

Estrogen in Girls and Women

The types and amounts of estrogen normally present in a woman’s blood will vary throughout her lifetime. Levels vary during each menstrual cycle, during pregnancy, and on a daily basis.

At Birth

Estradiol (E2) and estrone (E1) are high but fall within a few days. Concentration levels are minimal during early childhood.

At Puberty

Concentrations of estrone (E1) and estradiol (E2) begin to rise as puberty approaches. These estrogens are responsible for the development of breasts, uterine growth, and (with other hormones) the onset and regulation of menstruation. A moderate amount of estrone (E1) is present from puberty to menopause. This concentration will vary during the day but is otherwise relatively stable.

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.

During Menstruation

The menstrual cycle is approximately 28 days long and consists of two phases, follicular phase and luteal phase. During each cycle, estradiol (E2) and several other hormones normally rise and then fall in a specific sequence throughout the month. Your estrogen levels are highest in the middle of your menstrual cycle and lowest during your period.

During Pregnancy

Estriol (E3) is the primary estrogen present during pregnancy. It is produced by the placenta, starts to rise in the eighth week of pregnancy, and continues to rise throughout the pregnancy. A sharp increase of estriol (E3) occurs approximately 4 weeks prior to the onset of labor. Estriol (E3) circulating in maternal blood is quickly cleared out of the body. Each measurement of estriol is a snapshot of what is happening with the placenta and fetus, but there is also natural daily variation in estriol concentrations.

Estrone (E1) also rises during pregnancy, increasing as much as 10 fold between weeks 24 and 41. After delivery, estrone (E1) falls and estriol (E3) again becomes essentially undetectable.

During Menopause

Estrone (E1) is the primary estrogen present during menopause. Estradiol (E2) concentrations significantly decrease as ovarian production wanes and eventually stabilize at a low level.

Estrogen in Boys and Men

The types and amounts of estrogen normally present in a man’s blood change, but they vary much less over time than a woman’s and they are much lower. The concentration of estrogen in peripheral blood was typically very low in males ¹⁵⁾. Sizable quantities of estrogen were also found in testis ¹⁶⁾ and in semen ¹⁷⁾. In adult testes the consensus estrogen source was Leydig cells, which were thought to be the only testicular cell capable of estrogen synthesis ¹⁸⁾. However, the role of estrogens in the physiology of the male reproductive tract is still not fully understood ¹⁹⁾ and many questions remain unanswered, and future work will likely reveal further unexpected insights into the role that estrogens play in the male ²⁰⁾. The presence of estrogens in the male testis is well documented ²¹⁾, and there is clear evidence that estrogens exert a wide range of biological effects in men and not only in women ²²⁾.

Figure 2. Estrogen biosynthesis in males (biochemical pathway of testosterone conversion into estrogen)

What does estrogen do?

While estrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. Estrogens promote the development of female genital organs and features, growth of the endometrium, and inhibit the secretion of follicle-stimulating hormone (FSH) by the pituitary  and other aspects of regulating the menstrual cycle ²³⁾. In males, estrogen regulates certain functions of the reproductive system important to the maturation of sperm ²⁴⁾ and may be necessary for a healthy libido ²⁵⁾. The important actions of the endogenous estrogens are mediated by estrogen receptors (ERs), a dimeric nuclear protein that binds to DNA and controls gene expression. Estrogen receptors (ERs) are synthesized in many cell types in two protein forms, ERα and ERβ, which function as transcription factors once bound with their ligand. ERα is expressed in several tissues including uterus, prostate (stroma), ovary, testes, bone, breast, white adipose tissue, liver, and muscle, and ERβ is expressed in colon, prostate (epithelium), testes, salivary gland, bone marrow, and vascular endothelium ²⁶⁾.

Estrogens are primarily involved in the development and maintenance of normal sexual and reproductive function in women ²⁷⁾. Moreover, estrogens have also been shown to exert a wide range of biological effects in many physiological systems in both women and men ²⁸⁾. Estrogens mitigate post-injury disruption and inflammatory responses ²⁹⁾ and may play a protective role against oxidative stress ³⁰⁾ and muscle damage (by its antioxidant and membrane-stabilizing properties), repair, and inflammation ³¹⁾. Estradiol also affects satellite cell activation and proliferation, thereby enhancing the growth and recovery potential of cells ³²⁾. Moreover, myosin function is affected by age and by estradiol in women ³³⁾. Estrogens and ERs in the skeletal muscle cells of women ³⁴⁾ regulate carbohydrate and lipid metabolism. These receptors have been hypothesized to play a role on muscle strength ³⁵⁾ through the action by both estrogens and insulin-like growth factor (IGF)-1 ³⁶⁾.

Like other steroid hormones, estrogen enters passively into the cell where it binds to and activates the estrogen receptor. The estrogen:ER complex binds to specific DNA sequences called a hormone response element to activate the transcription of target genes (in a study using an estrogen-dependent breast cancer cell line as model, 89 such genes were identified) ³⁷⁾. Since estrogen enters all cells, its actions are dependent on the presence of the estrogen receptor (ER) in the cell. The estrogen receptor (ER) is expressed in specific tissues including the ovary, uterus and breast. The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of the estrogen receptor (ER) ³⁸⁾.

Overview of estrogen actions

• Structural
  • Mediate formation of female secondary sex characteristics
  • Accelerate metabolism
  • Increase fat store
  • Stimulate endometrial growth
  • Increase uterine growth
  • Increase vaginal lubrication
  • Thicken the vaginal wall
  • Maintenance of vessel and skin
  • Reduce bone resorption, increase bone formation
• Protein synthesis
  • Increase hepatic production of binding proteins
• Coagulation
  • Increase circulating level of factors 2, 7, 9, 10, plasminogen
  • Decrease antithrombin III
  • Increase platelet adhesiveness
• Lipid
  • Increase HDL, triglyceride
  • Decrease LDL, fat deposition
• Fluid balance
  • Salt (sodium) and water retention
  • Increase cortisol, sex hormone binding globulin (SHBG)
• Gastrointestinal tract
  • Reduce bowel motility
  • Increase cholesterol in bile
• Melanin
  • Increase pheomelanin, reduce eumelanin
• Cancer
  • Support hormone-sensitive breast cancers (see section below)
• Lung function
  • Promotes lung function by supporting alveoli (in rodents but probably in humans) ³⁹⁾
• Uterus lining
  • Estrogen together with progesterone promotes and maintains the uterus lining in preparation for implantation of fertilized egg and maintenance of uterus function during gestation period, also upregulates oxytocin receptor in myometrium
• Ovulation
  • Surge in estrogen level induces the release of luteinizing hormone, which then triggers ovulation by releasing the egg from the Graafian follicle in the ovary.
• Sexual behavior
  • Promotes sexual receptivity ⁴⁰⁾ and induces lordosis behavior ⁴¹⁾.
  • Regulates the stereotypical sexual receptivity behavior; this lordosis behavior is estrogen-dependent, which is regulated by the ventromedial nucleus of the hypothalamus ⁴²⁾
  • Sex drive is dependent on androgen levels ⁴³⁾ only in the presence of estrogen, but without estrogen, free testosterone level actually decreases sexual desire (instead of increases sex drive), as demonstrated for those women who have hypoactive sexual desire disorder, and the sexual desire in these women can be restored by administration of estrogen (using oral contraceptive) ⁴⁴⁾. In non-human mammals, mating desire is triggered by estrogen surge in estrus.

Female pubertal development

Estrogens are responsible for the development of female secondary sexual characteristics during puberty, including breast development, widening of the hips, and female fat distribution. Conversely, androgens are responsible for pubic and body hair growth, as well as acne and axillary odor.

Breast development

Estrogen, in conjunction with growth hormone (GH) and its secretory product insulin-like growth factor 1 (IGF-1), is critical in mediating breast development during puberty, as well as breast maturation during pregnancy in preparation of lactation and breastfeeding ⁴⁵⁾. Estrogen is primarily and directly responsible for inducing the ductal component of breast development ⁴⁶⁾, as well as for causing fat deposition and connective tissue growth. It is also indirectly involved in the lobuloalveolar component, by increasing progesterone receptor expression in the breasts ⁴⁷⁾ and by inducing the secretion of prolactin ⁴⁸⁾. Allowed for by estrogen, progesterone and prolactin work together to complete lobuloalveolar development during pregnancy ⁴⁹⁾.

Androgens such as testosterone powerfully oppose estrogen action in the breasts, such as by reducing estrogen receptor expression in them ⁵⁰⁾.

Female reproductive system

Estrogens are responsible for maturation and maintenance of the vagina and uterus, and are also involved in ovarian function, such as maturation of ovarian follicles. In addition, estrogens play an important role in regulation of gonadotropin secretion. For these reasons, estrogens are required for female fertility.

Brain and behavior

Sex drive

Estrogens are involved in libido (sex drive) in both women and men.

Cognition

Verbal memory scores are frequently used as one measure of higher level cognition. These scores vary in direct proportion to estrogen levels throughout the menstrual cycle, pregnancy, and menopause. Furthermore, estrogens when administered shortly after natural or surgical menopause prevents decreases in verbal memory. In contrast, estrogens have little effect on verbal memory if first administered years after menopause ⁵¹⁾. Estrogens also have positive influences on other measures of cognitive function ⁵²⁾. However the effect of estrogens on cognition is not uniformly favorable and is dependent on the timing of the dose and the type of cognitive skill being measured ⁵³⁾.

The protective effects of estrogens on cognition may be mediated by estrogens anti-inflammatory effects in the brain ⁵⁴⁾. Studies have also shown that the Met allele gene and level of estrogen mediates the efficiency of prefrontal cortex dependent working memory tasks ⁵⁵⁾.

Mental health

Estrogen is considered to play a significant role in women’s mental health. Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained low estrogen levels correlate with significant mood lowering. Clinical recovery from postpartum, perimenopause, and postmenopause depression has been shown to be effective after levels of estrogen were stabilized and/or restored ⁵⁶⁾.

Compulsions in male lab mice, such as those in obsessive-compulsive disorder (OCD), may be caused by low estrogen levels. When estrogen levels were raised through the increased activity of the enzyme aromatase in male lab mice, OCD rituals were dramatically decreased. Hypothalamic protein levels in the gene COMT are enhanced by increasing estrogen levels which are believed to return mice that displayed OCD rituals to normal activity. Aromatase deficiency is ultimately suspected which is involved in the synthesis of estrogen in humans and has therapeutic implications in humans having obsessive-compulsive disorder ⁵⁷⁾.

Local application of estrogen in the rat hippocampus has been shown to inhibit the re-uptake of serotonin. Contrarily, local application of estrogen has been shown to block the ability of fluvoxamine to slow serotonin clearance, suggesting that the same pathways which are involved in SSRI efficacy may also be affected by components of local estrogen signaling pathways ⁵⁸⁾.

Parenthood

Studies have also found that fathers had lower levels of cortisol and testosterone but higher levels of estrogen (estradiol) compared to non-fathers ⁵⁹⁾.

Binge eating

Estrogen may play a role in suppressing binge eating. Hormone replacement therapy using estrogen may be a possible treatment for binge eating behaviors in females. Estrogen replacement has been shown to suppress binge eating behaviors in female mice ⁶⁰⁾. The mechanism by which estrogen replacement inhibits binge-like eating involves the replacement of serotonin (5-HT) neurons. Women exhibiting binge eating behaviors are found to have increased brain uptake of neuron 5-HT, and therefore less of the neurotransmitter serotonin in the cerebrospinal fluid ⁶¹⁾. Estrogen works to activate 5-HT neurons, leading to suppression of binge like eating behaviors ⁶²⁾.

It is also suggested that there is an interaction between hormone levels and eating at different points in the female menstrual cycle. Research has predicted increased emotional eating during hormonal flux, which is characterized by high progesterone and estradiol levels that occur during the mid-luteal phase. It is hypothesized that these changes occur due to brain changes across the menstrual cycle that are likely a genomic effect of hormones. These effects produce menstrual cycle changes, which result in hormone release leading to behavioral changes, notably binge and emotional eating. These occur especially prominently among women who are genetically vulnerable to binge eating phenotypes ⁶³⁾.

Binge eating is associated with decreased estradiol and increased progesterone ⁶⁴⁾. Klump et al. ⁶⁵⁾ Progesterone may moderate the effects of low estradiol (such as during dysregulated eating behavior), but that this may only be true in women who have had clinically diagnosed binge episodes. Dysregulated eating is more strongly associated with such ovarian hormones in women with binge episodes than in women without binge episodes ⁶⁶⁾.

The implantation of 17β-estradiol pellets in ovariectomized mice significantly reduced binge eating behaviors and injections of GLP-1 in ovariectomized mice decreased binge-eating behaviors ⁶⁷⁾.

The associations between binge eating, menstrual-cycle phase and ovarian hormones correlated ⁶⁸⁾.

Bone/skeletal system

Estrogens are responsible for both the pubertal growth spurt, which causes an acceleration in linear growth, and epiphyseal closure, which limits height and limb length, in both females and males. In addition, estrogens are responsible for bone maturation and maintenance of bone mineral density throughout life. Due to hypoestrogenism, the risk of osteoporosis increases during menopause.

Cardiovascular system

Women suffer less from heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis ⁶⁹⁾. It also helps in maintaining the delicate balance between fighting infections and protecting arteries from damage thus lowering the risk of cardiovascular disease ⁷⁰⁾.

Immune system

Estrogen has anti-inflammatory properties and helps in mobilization of polymorphonuclear white blood cells or neutrophils ⁷¹⁾.

Associated conditions

Estrogens are implicated in various estrogen-dependent conditions, such as ER-positive breast cancer, as well as a number of genetic conditions involving estrogen signaling or metabolism, such as estrogen insensitivity syndrome, aromatase deficiency, and aromatase excess syndrome.

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 migraine, 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.

How to increase estrogen

Estrogen foods

Table 1. Foods high in phytoestrogens

[Sources ⁷²⁾, ⁷³⁾, ⁷⁴⁾]

Table 2. Isoflavone content of a representative sample of food products including soy based products

[Source ⁷⁵⁾]

Estrogen pills

Estrogen is used in some medicines, including some contraceptives and menopause medications.

In the US, the combined oral contraceptive pill (‘birth control pill’) contains a synthetic version of estrogen. Another type of contraception, the vaginal ring, also contains estrogen. These contraceptives work mainly by preventing the release of eggs from the ovaries.

If you are having problems with menopause symptoms, such as hot flushes and mood swings, you may choose to go on hormone replacement therapy (HRT). HRT includes estrogen taken in the form of a tablet, gel or skin patch, and can be very effective in easing menopausal symptoms.

Estrogen side effects

Side effects of estrogens include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema among others ⁷⁶⁾. Other side effects of estrogens include an increased risk of blood clots, cardiovascular disease, and, when combined with most progestogens, breast cancer ⁷⁷⁾. In men, estrogens can cause breast development, feminization, infertility, low testosterone levels, and sexual dysfunction among others.

High estrogen

Women

High estrogen symptoms:

• 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

Men

High estrogen in men can cause:

• Enlarged breasts (gynecomastia)
• Poor erections
• Infertility

Estrogen blocker

Antiestrogen or estrogen receptor blocker (e.g. Tamoxifen) binds to estrogen receptors and inhibit the action of estrogen. Estrogen controls the growth of certain types of breast cancers called estrogen receptor positive cancers. So estrogen blockers (estrogen receptor antagonists) are useful in treating patients with estrogen sensitive breast cancers. Tamoxifen blocks the activity of estrogen (a female hormone) in the breast. This may stop the growth of some breast tumors that need estrogen to grow. However, the exact way that tamoxifen works against breast cancer is not known, but it may be related to the way it blocks the effects of estrogen on the body.

Tamoxifen is used to treat breast cancer that has spread to other parts of the body in men and women. It may also be used to treat other kinds of cancer, as determined by your doctor. Tamoxifen is used to treat early breast cancer in women who have already been treated with surgery, radiation, and/or chemotherapy. Tamoxifen is used to reduce the risk of developing a more serious type of breast cancer in women who have had ductal carcinoma in situ (DCIS; a type of breast cancer that does not spread outside of the milk duct where it forms) and who have been treated with surgery and radiation.

Tamoxifen may also be used to reduce the risk of developing breast cancer in women who have a high risk of developing breast cancer due to their age, personal medical history, and family medical history. Women at high risk for developing breast cancer are at least 35 years of age and have a combination of risk factors that make their chance of developing breast cancer 1.67% or more over the next 5 years. Your doctor will help to determine your risk of developing breast cancer.

The following are risk factors that may increase your chance of developing breast cancer:

• If you have close family members (mother, sister, or daughter) with breast cancer.
• If you have ever had a breast biopsy or if high-risk changes in your breast(s) have been found from a breast biopsy.
• If you have never been pregnant or if your first pregnancy occurred at a late age.
• If your first menstrual period occurred at an early age.

Before you begin treatment with tamoxifen, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

Tamoxifen is available only with your doctor’s prescription.

This product is available in the following dosage forms:

• Solution
• Tablet

Tamoxifen comes as a tablet to take by mouth. Tamoxifen is usually taken once or twice a day with or without food. Take tamoxifen at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain anything you do not understand. Take tamoxifen exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow tamoxifen tablets whole; do not split, chew, or crush them. Swallow the tablets with water or any other nonalcoholic drink.

If you are taking tamoxifen to prevent breast cancer, you will probably take it for five years. If you are taking tamoxifen to treat breast cancer, your doctor will decide how long your treatment will last. Do not stop taking tamoxifen without talking to your doctor.

If you forget to take a dose of tamoxifen, take the missed dose as soon as you remember it, and take your next dose as usual. However, if it is almost time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Other uses of antiestrogen

Tamoxifen is also used sometimes to induce ovulation (egg production) in women who do not produce eggs but wish to become pregnant. Tamoxifen is also sometimes used to treat McCune-Albright syndrome (a condition that may cause bone disease, early sexual development, and dark colored spots on the skin in children). Talk to your doctor about the possible risks of using this drug for your condition.

Tamoxifen may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking tamoxifen:

• tell your doctor and pharmacist if you are allergic to tamoxifen or any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: aminoglutethimide (Cytadren); anastrazole (Arimidex), bromocriptine (Parlodel); cancer chemotherapy medication such as cyclophosphamide (Cytoxan, Neosar) letrozole (Femara); medroxyprogesterone (Depo-Provera, Provera, in Prempro); phenobarbital; and rifampin (Rifadin, Rimactane). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• in addition to the conditions listed in the IMPORTANT WARNING section, tell your doctor if you have or have ever had high blood levels of cholesterol.
• tell your doctor if you are pregnant or plan to become pregnant. You should not plan to become pregnant while taking tamoxifen or for 2 months after your treatment. Your doctor may perform a pregnancy test or tell you to begin your treatment during your menstrual period to be sure that you are not pregnant when you begin taking tamoxifen. You will need to use a reliable nonhormonal method of birth control to prevent pregnancy while you are taking tamoxifen and for 2 months after your treatment. Talk to your doctor about the types of birth control that are right for you, and continue to use birth control even if you do not have regular menstrual periods during your treatment. Stop taking tamoxifen and call your doctor right away if you think you have become pregnant during your treatment. Tamoxifen may harm the fetus.
• tell your doctor if you are breast-feeding. You should not breastfeed during your treatment with tamoxifen.
• tell all of your doctors and other health care providers that you are taking tamoxifen.
• you will still need to look for early signs of breast cancer since it is possible to develop breast cancer even during treatment with tamoxifen. Talk to your doctor about how often you should examine your breasts yourself, have a doctor examine your breasts, and have mammograms (x-ray examinations of the breasts). Call your doctor right away if you find a new lump in your breast.

Antiestrogen side effects

Tamoxifen may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• increased bone or tumor pain
• pain or reddening around the tumor site
• hot flashes
• nausea
• excessive tiredness
• dizziness
• depression
• headache
• thinning of hair
• weight loss
• stomach cramps
• constipation
• loss of sexual desire or ability (in men)

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• vision problems
• loss of appetite
• yellowing of the skin or eyes
• unusual bruising or bleeding
• fever
• blisters
• rash
• swelling of the eyes, face, lips, tongue, throat, hands, arms, feet, ankles, or lower legs
• thirst
• muscle weakness
• restlessness

Tamoxifen may increase the risk that you will develop other cancers, including liver cancer. Talk to your doctor about this risk.

Tamoxifen may increase the risk that you will develop cataracts (clouding of the lens in the eye) that may need to be treated with surgery. Talk to your doctor about this risk.

Tamoxifen may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

Symptoms of overdose may include:

• uncontrollable shaking of a part of the body
• unsteadiness
• dizziness