INTRODUCTION — Menstrual cycle disorders can cause a woman's periods to be absent or infrequent. Although some women do not mind missing their menstrual period, these changes should always be discussed with a healthcare provider because they can signal underlying medical conditions and have long-term health consequences. A woman who misses more than three menstrual periods (either consecutively or over the course of a year) should see a healthcare provider.
DEFINITIONS
Amenorrhea — Amenorrhea refers to the absence of menstrual periods, and is classified as primary (when menstrual periods have not started by age 16) or secondary (when menstrual periods are absent for more than three to six months in a woman who previously had periods).
Oligomenorrhea — Oligomenorrhea refers to infrequent menstrual periods (fewer than six to eight periods per year).
The causes, evaluation, and treatment of amenorrhea and oligomenorrhea are similar, and will be discussed together.
CAUSES — The brain (including the pituitary gland), ovaries, and uterus normally follow a sequence of events once per month; this sequence helps to prepare the body for pregnancy. Two hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), are made by the pituitary gland. Two other hormones, progesterone and estrogen, are made by the ovaries.
During the first half of the cycle, small increases in FSH stimulate the ovary to develop a follicle (cyst) that contains an egg (oocyte). The follicle produces rising levels of estrogen, which cause the lining of the uterus to thicken and the pituitary to release a very large amount of LH. This midcycle "surge" of LH causes the egg to be released from the ovary (called ovulation, show figure 1).
Menstrual cycle disorders can result from conditions that affect the hypothalamus, pituitary gland, ovaries, uterus, cervix, or vagina.
Primary amenorrhea — Many of the conditions that cause primary amenorrhea are present at birth, but may not be noticed until puberty. These conditions include genetic or chromosomal abnormalities and structural abnormalities (eg, if the uterus is not present or developed abnormally) of the reproductive tract.
Functional hypothalamic amenorrhea can also cause primary amenorrhea. This occurs when the hypothalamus slows or stops releasing GnRH (gonadotropin releasing hormone), a hormone that influences when a woman has a menstrual period. The hypothalamus is sensitive to many factors, including low body weight (defined as weighing 10 percent below ideal body weight, show table 1A-1B), having very little body fat, a very low calorie or fat intake, emotional stress, strenuous exercise, and some medical conditions or illnesses. When GnRH production slows or stops, a woman may stop having regular menstrual periods. For example, a woman who is training to run a marathon may stop menstruating until she is no longer training intensively.
Other causes of primary amenorrhea, such as prolactin-secreting tumors of the pituitary gland, are less common. All of the conditions that lead to secondary amenorrhea can also cause primary amenorrhea.
Secondary amenorrhea — Pregnancy is the most common of secondary amenorrhea. Among nonpregnant women, ovarian conditions are the most common cause of secondary amenorrhea; these conditions include polycystic ovary syndrome and ovarian failure (early menopause).
Functional hypothalamic amenorrhea is also a common cause of secondary amenorrhea (see above).
Prolactin-secreting pituitary tumors are another common cause of secondary amenorrhea. (See "Patient information: Lactotroph adenomas (prolactinomas)").
Oligomenorrhea — Many of the conditions that cause primary or secondary amenorrhea can also cause oligomenorrhea. However, most women who develop infrequent periods have polycystic ovary syndrome (see "Polycystic ovary syndrome" below).
EVALUATION — The approach to evaluating amenorrhea/oligomenorrhea will depend upon a woman's medical history and the results of a physical examination.
History — There are often clues about the cause of amenorrhea in a woman's personal and family medical history. Factors to consider include health during infancy and childhood, sexual development during puberty, as well as the family's growth and puberty patterns. The menstrual history will also be reviewed, including when the first period started (if there was a first period) and how frequently periods have occurred since.
Other important points include the presence of discharge from the breasts, hot flashes, masculine features, and headaches or impaired vision. The clinician will also ask about any medications, herbs, and vitamins used, recent stress, recent gynecologic procedures and events, changes in weight, diet, or exercise patterns, and any illnesses.
Physical examination — A physical examination can provide information about growth and sexual development, hormonal status, reproductive tract anatomy, and the presence of other medical conditions, such as thyroid disease or diabetes (both of which can cause menstrual cycle problems).
During a physical examination, the clinician will note the woman's height, weight, and arm span (measurement of length, when arms are extended, from one side to the other). The clinician will examine the thyroid gland, evaluate breast development, and perform a pelvic examination.
Testing — Depending upon the history and physical examination, the clinician may order laboratory test. Because pregnancy is the most common cause of secondary amenorrhea, a pregnancy test is usually recommended for women whose menstrual periods have stopped, even if the results of a home pregnancy test are negative. Blood tests to measure hormone levels may also be ordered.
In selected cases, magnetic resonance imaging (MRI) may be done to determine if there are hypothalamic or pituitary gland abnormalities. In women with a suspected chromosomal abnormality, a chromosome analysis may be recommended. A pelvic ultrasound is recommended to identify potential structural abnormalities of the uterus, cervix, and vagina.
TREATMENT — The goal of treatment is to correct the underlying condition. For a woman who is trying to become pregnant, returning fertility may be another goal.
The type and result of treatment depends upon the underlying cause of amenorrhea. In some cases, the results of the evaluation are unexpected (such as early menopause) and can be distressing; in these situations, counseling with a social worker or psychotherapist may be of benefit.
Anatomic problems — Surgery is often an effective treatment if amenorrhea is caused by an obstruction of the reproductive tract. Examples of obstructions that cause amenorrhea or oligomenorrhea include an imperforate hymen or vaginal septum. In both cases, corrective surgery is needed.
Imperforate hymen — The hymen is the tissue that surrounds the vaginal opening; some young girls lack an opening in the hymen, which causes menstrual blood to collect in the vagina.
Vaginal septum — A vaginal septum is a band of tissue that divides the vagina, either longitudinally or transversely. A transverse vaginal septum is similar to an imperforate hymen because it blocks the flow of menstrual blood, causing it to collect in the vagina.
In rare cases, evaluation may reveal underdeveloped or completely absent structures of the female reproductive tract (such as the vagina or uterus). These anatomic problems are usually caused by chromosomal abnormalities, and treatment options are limited.
Ovarian failure — Normally, a woman's ovaries stop releasing eggs around the age of 50; this is called menopause. If a woman's ovaries stop releasing eggs before age 40, this is called premature ovarian failure. When the ovaries fail, estrogen production stops, leading to amenorrhea and the symptoms and health risks associated with menopause.
Although the ovarian production of eggs cannot be restored , hormone replacement therapy (HRT) with estrogen and progesterone (or a hormonal contraceptive such as a birth control pill) can help prevent or treat many of the symptoms and long-term health consequences, such as hot flashes, vaginal dryness, and osteoporosis. HRT has risks of its own. However, a young (20 to 50 year old) woman who takes HRT does not have the same risks as a woman who is greater than 50 years old and takes HRT. Women considering this option should discuss the pros and cons with their healthcare provider. (See "Patient information: Postmenopausal hormone therapy and breast cancer").
Turner's syndrome — Women with Turner's syndrome have a chromosomal abnormality that causes ovarian failure at an extremely young age (before puberty). However, hormone replacement that begins at puberty can lead to normal breast development and menstrual cycles (induced by the hormones). Women with Turner's syndrome have a normal uterus.
With most types of ovarian failure, pregnancy can be achieved using donor eggs.
Polycystic ovary syndrome — Polycystic ovary syndrome (PCOS) is a chronic condition that causes infrequent periods and an excess of androgens (male hormones); this often leads to acne and excessive facial hair. Women with PCOS can also have problems with high cholesterol levels and obesity. Most healthcare providers recommend medical treatment to alleviate the symptoms of androgen excess, reestablish normal menstrual cycles, and prevent the long-term complications of this disorder (an increased risk of type 2 diabetes and possibly coronary heart disease). (See "Patient information: Polycystic ovary syndrome (PCOS)").
Functional hypothalamic amenorrhea — Women who have functional hypothalamic amenorrhea may resume having normal menstrual periods with certain lifestyle changes, including increasing caloric and/or fat intake, gaining weight, reducing the intensity or frequency of exercise, and resolving emotional stress. Low body weight and/or nutritional deficiencies — Women with eating disorders such as anorexia nervosa or bulimia often need specialized care. This usually includes nutrition counseling and work with eating disorder specialists. Strenuous exercise — Although exercise offers wonderful health benefits, exercising frequently or excessively can lead to amenorrhea and infertility. Studies suggest that amenorrhea develops when a woman's caloric intake is less than she burns with exercise and other daily activities, or when a woman's percentage of body fat drops below a critical level. Most women with amenorrhea associated with exercise have also lost weight (resulting in a weight less than 10 percent of the ideal body weight, show table 1A-1B).
For women with exercise-associated amenorrhea, the primary treatments include increasing calorie intake and reducing the frequency and/or intensity of exercise. These measures are particularly important if a woman is trying to become pregnant. All exercising women with amenorrhea should be sure they eat 1200 to 1500 mg of calcium daily (or take a calcium supplement) and should take a vitamin D supplement (400 IU daily). (See "Patient information: Calcium for bone health").
Some clinicians recommend estrogen and progestin hormone replacement (or a hormonal contraceptive such as a birth control pill) for women with amenorrhea who do not wish to cut back on exercise or increase caloric intake. Nonhormonal medications may be recommended to minimize potential bone loss. (See "Patient information: Osteoporosis prevention and treatment").
Hypothalamic or pituitary conditions — Some hypothalamic and pituitary gland conditions that cause amenorrhea, such as a congenital deficiency of gonadotropin-releasing hormone (GnRH), are irreversible. However, women with these conditions can have menstrual periods and become pregnant when treated with gonadotropins or gonadotropin-releasing hormone (GnRH). These hormones require a daily injection, and function to induce ovulation.
Hyperprolactinemia — Women with amenorrhea and hyperprolactinemia can usually regain normal menstrual periods and become pregnant when treated with medications called dopamine agonists (bromocriptine and cabergoline are examples).
Endometrial adhesions (Asherman syndrome) — Some gynecologic procedures, such as a dilatation and curettage (D&C), can result in formation of adhesions (a type of scar tissue) which damage the uterine lining. If adhesion formation is so extensive that most or all of the normal endometrium is replaced by adhesions, then menstrual blood loss will be reduced or stop. A clinician may recommend surgery to remove the scarred tissue, which is followed by estrogen treatment to stimulate regrowth of the lining. (See "Patient information: Dilation and curettage (D&C)").
Other medical conditions — Treatment of medical conditions, such as hypothyroidism and diabetes mellitus, may restore normal menstrual periods in women with amenorrhea.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
American Academy of Family Physicians
(www.familydoctor.org)
The Nemours Foundation
(www.kidshealth.org, search for menstrual)
The Hormone Foundation
(www.hormone.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Laufer, MR, Floor, AE, Parsons, KE, et al. Hormone testing in women with adult-onset amenorrhea. Gynecol Obstet Invest 1995; 40:200.
2. Laughlin, GA, Dominguez, CE, Yen, SS. Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1998; 83:25.
3. Loucks, AB, Vaitukaitis, J, Cameron, JL, et al. The reproductive system and exercise in women. Med Sci Sports Exerc 1992; 24:S288.
4. Warren, MP, Voussoughian, F, Geer, EB, et al. Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating. J Clin Endocrinol Metab 1999; 84:873.
Monday, October 15, 2007
Menorrhagia (excessive menstrual bleeding)
INTRODUCTION — In a normal menstrual cycle, the average woman loses about 2 to 3 tablespoons (35 to 40 milliliters) of blood. However, some women lose much larger amounts of blood. Menorrhagia is the medical term for excessive or prolonged menstrual bleeding.
Women who lose 5 to 6 tablespoons (about 80 milliliters) of blood or more during their menstrual period are said to have menorrhagia. Losing a lot of blood during the menstrual period can cause medical problems and lifestyle issues. As an example, more than 50 percent of women with menorrhagia develop iron deficiency anemia (lower than normal amounts of red blood cells). Extremely heavy bleeding may interfere with a woman's life because of the frequent need to change pads or tampons and because heavy bleeding can cause painful menstrual cramps.
THE NORMAL MENSTRUAL CYCLE — Most women's menstrual cycle lasts between 24 and 35 days; the average is 28 days. During this time, the uterus, ovaries, hypothalamus, and pituitary gland follow a sequence of events that prepares the body for pregnancy. Two hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), are made by the pituitary gland. These hormones stimulate the ovary to make two other hormones, progesterone and estrogen.
During the first half of the cycle, FSH stimulates a follicle to develop in one of the ovaries. This causes the estrogen level to rise, causing the lining of the uterus to grow and thicken (show figure 1). These events stimulate a risk in the LH level, which ultimately causes the follicle to release an egg from the ovary (called ovulation).
After ovulation, the ovary produces both estrogen and progesterone, which prepare the uterus for possible implantation and pregnancy. Progesterone also helps to "stabilize" the lining of the uterus, preventing abnormal bleeding. If pregnancy does not occur, estrogen and progesterone levels drop and the lining of the uterus is shed. The process of shedding is called the menstrual period. The menstrual blood contains blood as well as tissue from inside the uterus. Most women lose 2 to 3 tablespoons of blood over 3 to 7 days.
CAUSES — In women with menorrhagia, the sequence of events that leads to the menstrual period may be normal but bleeding is excessive because of an abnormal uterus (eg, due to abnormal growths) or because of a problem with blood clotting. In other women with menorrhagia, this sequence of events is abnormal because ovulation does not occur.
Anovulation — Anovulation occurs when a woman's ovaries fail to produce and release an egg (ovulate) once per month. Since the normal hormonal changes of ovulation do not occur, the lining of the uterus (called the endometrium) does not uniformly shed and regrow as in a normal menstrual cycle. Instead, excessive estrogen stimulates the lining of the uterus (endometrium) to continue growing and become thicker. Progesterone is not present at the usual levels, which causes the lining to shed irregularly, which results in heavy and/or prolonged bleeding.
Menorrhagia in adolescents is usually caused by anovulation. Anovulatory bleeding is also common before menopause (called perimenopause) and with some endocrine disorders, such as hypothyroidism and polycystic ovary syndrome. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Bleeding tendency — Menorrhagia can result from conditions that prevent the blood from clotting normally. Some examples are von Willebrand disease, low platelet count or platelet dysfunction, and use of anticoagulants ("blood thinners") such as warfarin. (See "Patient information: Warfarin (Coumadin®)").
Uterine growths — When adult women experience menorrhagia, it is often due to a benign growth in the uterus. The most common growths are: Polyps, which are small grape-like growths of the lining of the uterus. Fibroids or leiomyomas, which are benign tumors involving the muscular walls of the uterus (myometrium) Adenomyosis, which refers to the growth of endometrial-like tissue within the muscular walls of the uterus
Rarely, cancer of the endometrium or myometrium can cause menorrhagia.
SIGNS AND SYMPTOMS — Women with menorrhagia typically have one or more of the following: Need to change pads/tampons more frequently than every three hours or use more than 21 pads/tampons during a period Need to use both pads and tampons to absorb menstrual flow Need to change pads or tampons during the night to absorb menstrual flow Pass blood clots larger than 1 inch Iron-deficiency anemia
DIAGNOSIS — If a healthcare provider suspects menorrhagia based on the woman's description of her bleeding, he or she will try to determine the cause by performing a medical history and physical examination. The physical examination is done to look for signs of bleeding elsewhere in the body, which could indicate a bleeding disorder. A pelvic examination will be done to determine the size and shape of the uterus. In women with fibroids, the uterus is often enlarged or irregularly shaped. An endometrial biopsy, in which a small sample of the uterine lining is removed, may be recommended in certain situations.
Laboratory tests may be recommended to look for bleeding disorders or thyroid disease. In some cases, the provider may recommend imaging tests, most commonly a pelvic ultrasound, to look for endometrial polyps, fibroids, or adenomyosis.
MEDICAL TREATMENT — The treatment of menorrhagia depends upon the cause and severity of the condition, the patient's preferences, the need to prevent pregnancy currently, and the woman's desire to have children in the future. Providers generally recommend that women with menorrhagia first try medical treatment (using medications). If one or more medical treatments are not successful, a surgical treatment may be recommended.
Combined oral contraceptives — Use of combined (estrogen and progesterone) oral contraceptives decreases menstrual blood loss over time. Alternatively, contraceptive patches or rings may be used instead of pills. All of these methods also help to prevent pregnancy. Combined oral contraceptives need to be taken daily.
Continuous dosing — Pills may be taken so that the woman has a period once per month or once every three to four months (called continuous dosing). This regimen is a particularly good treatment for women with painful periods. In this regimen, the woman takes the first three weeks of a pill pack, then immediately starts a new pack (without a break); the last week of (placebo) pills is not used. This can be continued for as long as desired.
Seasonale® is an extended cycle oral contraceptive product in which an active pill is taken every day for 12 weeks, followed by seven days of inactive (placebo) pills. Seasonique® is also an extended cycle oral contraceptive, although it contains seven days of a low dose estrogen pills instead of the placebo pills; this is intended to reduce breakthrough bleeding and estrogen withdrawal symptoms.
Taking an oral contraceptive for an extended time results in fewer periods per year, although many women experience breakthrough bleeding when starting this regimen. Breakthrough bleeding is inconvenient, but does not mean that there is an increased risk of pregnancy (unless pills are forgotten). (See "Patient information: Hormonal methods of birth control").
Progesterone — Progesterone is a hormone made by the ovary that is effective in preventing excessive bleeding in women with chronic anovulation. A synthetic form of progesterone, called progestin, can be given as a pill, injection, implant under the skin, or an intrauterine contraceptive. Progestin pills do not prevent pregnancy while the injection, implant, and intrauterine contraceptive do prevent pregnancy.
Pills — Progestin pills are usually taken for 11 to 14 days each month; within two weeks of the last pill, most women will begin to have a withdrawl bleed. Pills may be recommended every one to three months and help to prevent the uterine lining from becoming overly thickened, which can cause excessive bleeding. Progestin pills do not prevent pregnancy and are not useful for menorrhagia caused by adenomyosis, polyps, or fibroids.
Injection — Medroxyprogesterone acetate (Depo-Provera®) is a long-acting progestin that is injected deep into a muscle, such as the buttock or upper arm, once every three months. A similar preparation can be given subcutaneously (under the skin). Depo-Provera can reduce bleeding in women with menorrhagia, and it also is a very effective form of birth control; it prevents pregnancy for at least 12 weeks per dose. Because it is long-acting, it may not be ideal for women who wish to become pregnant shortly after stopping the medication. Although most women are able to conceive within 10 months, fertility may not return for up to 18 months after the last injection.
The most common side effects of Depo-Provera are irregular or prolonged bleeding and spotting, particularly during the first few months of use. Up to 50 percent of women completely stop having menstrual periods (amenorrhea) after one year of use. Menses generally return within six months of the last injection. Depo-Provera can cause weight gain and thinning of the bones in some women.
Intrauterine contraceptive — An intrauterine contraceptive (IUC) is a device that is made of molded plastic and coated with progestin (show picture 1). The IUC is inserted into a woman's uterus by a healthcare provider. A thin plastic string is attached to the device and can be felt inside the vagina. In the United States, the progestin-releasing IUC is called Mirena®. It is effective in reducing bleeding and preventing pregnancy for up to five years. The IUC is different than an intrauterine device (IUD), which is often coated with copper and causes heavier menstrual bleeding.
In one study, the Mirena reduced menstrual blood loss by as much as 97 percent after a year of use [1]. The most bothersome side effect was spotting during the first three months after the IUC was inserted; by six months, the majority of women had no bleeding or infrequent light bleeding. The progesterone releasing IUC is the most effective medical treatment for menorrhagia, is relatively inexpensive, and helps at least 60 percent of women to avoid surgical treatments for menorrhagia.
Implant — A single-rod progestin implant, Implanon®, has been approved for use in the US and elsewhere. A healthcare provider inserts it under the skin in the upper inner arm (show picture 2). It prevents pregnancy and can control bleeding for up to three years. However, the implant can be removed sooner if pregnancy is desired. Insertion and removal can be done in an office or clinic. It is effective within 24 hours of insertion. Irregular bleeding is the most bothersome side effect. Fertility returns rapidly after removal of the rod.
Nonsteroidal anti-inflammatory drugs (NSAIDs) — Nonsteroidal anti-inflammatory drugs, such as ibuprofen (Motrin® and Advil®) and mefenamic acid (Ponstel®), can help relieve the pain of menstrual cramping and reduce blood flow. NSAIDs are relatively inexpensive, have few side effects, and only need to be taken for three to five days during the menstrual period. However, some women find that NSAIDs cause stomach upset.
Gonadotropin-releasing hormone (GnRH) agonists — GnRH agonists may be used to temporarily control bleeding in women who are waiting to have a surgical treatment. Gonadotropin releasing hormone (GnRH) agonists (eg, nafarelin, leuprolide, goserelin) work by turning off ovarian production of estrogen, thereby causing a temporary type of menopause. The lack of estrogen causes the lining of the uterus to shrink and reduces pain in over 80 percent of patients. The drugs may be given as a nasal spray, implant, or injection.
The full dose of a GnRH agonist is usually taken for up to six months; they are not usually taken for longer due to the risk of bone thinning. Side effects of GnRH agonists include headaches in 20 percent of women, especially in patients with a history of migraine, and the signs and symptoms of menopause: lack of menstrual bleeding, hot flashes, vaginal dryness, decreased libido, insomnia, and loss of bone density (on average a 2 to 7 percent loss). Bone strength recovers substantially after the drug is stopped.
Many of these side effects can be minimized by giving estrogen or a bone strengthening drug along with the GnRH agonist. This treatment is not a permanent solution because heavy bleeding usually resumes when the drug is stopped.
Antifibrinolytic agents — Drugs like tranexamic acid and aminocaproic acid only need to be taken on the days of menses, do not interfere with fertility, and, since they act within two to three hours of administration, can also be used for acute control of bleeding. However, some women experience side effects, such as stomach problems, leg cramps, dizziness, and headaches, when they take these medications.
Danazol — Danazol is a medication that increases the level of androgens (male type hormone) and decreases the level of estrogen. This temporarily stops the menstrual period by inhibiting ovulation and ovarian production of estrogen and by shrinking the endometrium.
The medication is taken by mouth at a dose of 200 to 400 mg two to four times per day for 6 months or more. However, there is a high (75 percent) incidence of one or more side effects. Side effects may include weight gain, edema, decreased breast size, acne, oily skin, hirsutism (male pattern hair growth), deepening of the voice, headache, hot flashes, changes in libido, and mood changes. All of these changes are reversible, except for voice changes; however, a return to normal may take many months.
Danazol should not be taken by women with certain types of liver, kidney, and heart disease because these disorders may worsen. Women who could become pregnant must use a nonhormonal form of birth control (eg, condoms) while taking danazol because of a serious risk of birth defects if danazol is taken during pregnancy. (See "Patient information: Barrier methods of birth control").
SURGICAL TREATMENT — For women who have known abnormalities of the uterus that are known to cause menorrhagia, such as polyps or fibroids, surgical removal of these lesions often cures the menorrhagia. Some fibroids may also be treated by cutting off their blood supply. This procedure is called uterine artery embolization, and is discussed in depth in a separate topic review. (See "Patient information: Fibroids").
The two major surgical treatments for menorrhagia are:
Endometrial ablation — In this procedure, a physician destroys or removes most of the lining of the uterus. There are several methods of endometrial ablation, all of which use an instrument that is inserted through the cervix and into the uterine cavity. The procedure is usually done in a day surgery or office setting. To reduce pain, a sedative medication is given and local anesthesia is injected into the cervix. The most common postoperative side effects are cramping, vaginal discharge, and nausea. A pinkish vaginal discharge is present for two to three days after the procedure; this gradually becomes clear and watery discharge that lasts for two to 10 days. Uterine cramping may persist for 24 to 72 hours. Most women can resume their normal activities within a short time.
Endometrial ablation reduces and often eliminates menstrual blood flow in women with menorrhagia. However, it is not an option for women who may want to become pregnant in the future because the damage to the endometrium often prevents pregnancy.
A second endometrial ablation may be needed if symptoms persist or recur; between 5 and 20 percent of women who have this procedure have a second endometrial ablation to control uterine bleeding within three to five years of the initial procedure. In addition, 9 to 15 percent undergo a hysterectomy for persistent or new uterine symptoms.
Hysterectomy — Hysterectomy is surgical removal of the uterus. This is a permanent and complete treatment of menorrhagia since the source of bleeding (the uterus) is completely removed. However, hysterectomy is a major surgical procedure that has more complications and a longer recovery period than endometrial ablation. Pregnancy is not possible after hysterectomy. (See "Patient information: Abdominal hysterectomy" and see "Patient information: Vaginal hysterectomy").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Women's Health Information Center
(www.4women.gov)
The Mayo Clinic
(www.mayoclinic.com)
[2-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Andersson, JK, Rybo, G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 1990; 97:690.
2. Warner, PE, Critchley, HO, Lumsden, MA, et al. Menorrhagia I: Measured blood loss, clinical features, and outcome in women with heavy periods: A survey with follow-up data. Am J Obstet Gynecol 2004; 190:1216.
3. Iyer, V, Farquhar, C, Jepson, R. Oral contraceptive pills for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; :CD000154.
4. Lethaby, AE, Cooke, I, Rees, M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005; :CD002126.
5. Marjoribanks, J, Lethaby, A, Farquhar, C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev 2003; :CD003855.
Women who lose 5 to 6 tablespoons (about 80 milliliters) of blood or more during their menstrual period are said to have menorrhagia. Losing a lot of blood during the menstrual period can cause medical problems and lifestyle issues. As an example, more than 50 percent of women with menorrhagia develop iron deficiency anemia (lower than normal amounts of red blood cells). Extremely heavy bleeding may interfere with a woman's life because of the frequent need to change pads or tampons and because heavy bleeding can cause painful menstrual cramps.
THE NORMAL MENSTRUAL CYCLE — Most women's menstrual cycle lasts between 24 and 35 days; the average is 28 days. During this time, the uterus, ovaries, hypothalamus, and pituitary gland follow a sequence of events that prepares the body for pregnancy. Two hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), are made by the pituitary gland. These hormones stimulate the ovary to make two other hormones, progesterone and estrogen.
During the first half of the cycle, FSH stimulates a follicle to develop in one of the ovaries. This causes the estrogen level to rise, causing the lining of the uterus to grow and thicken (show figure 1). These events stimulate a risk in the LH level, which ultimately causes the follicle to release an egg from the ovary (called ovulation).
After ovulation, the ovary produces both estrogen and progesterone, which prepare the uterus for possible implantation and pregnancy. Progesterone also helps to "stabilize" the lining of the uterus, preventing abnormal bleeding. If pregnancy does not occur, estrogen and progesterone levels drop and the lining of the uterus is shed. The process of shedding is called the menstrual period. The menstrual blood contains blood as well as tissue from inside the uterus. Most women lose 2 to 3 tablespoons of blood over 3 to 7 days.
CAUSES — In women with menorrhagia, the sequence of events that leads to the menstrual period may be normal but bleeding is excessive because of an abnormal uterus (eg, due to abnormal growths) or because of a problem with blood clotting. In other women with menorrhagia, this sequence of events is abnormal because ovulation does not occur.
Anovulation — Anovulation occurs when a woman's ovaries fail to produce and release an egg (ovulate) once per month. Since the normal hormonal changes of ovulation do not occur, the lining of the uterus (called the endometrium) does not uniformly shed and regrow as in a normal menstrual cycle. Instead, excessive estrogen stimulates the lining of the uterus (endometrium) to continue growing and become thicker. Progesterone is not present at the usual levels, which causes the lining to shed irregularly, which results in heavy and/or prolonged bleeding.
Menorrhagia in adolescents is usually caused by anovulation. Anovulatory bleeding is also common before menopause (called perimenopause) and with some endocrine disorders, such as hypothyroidism and polycystic ovary syndrome. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Bleeding tendency — Menorrhagia can result from conditions that prevent the blood from clotting normally. Some examples are von Willebrand disease, low platelet count or platelet dysfunction, and use of anticoagulants ("blood thinners") such as warfarin. (See "Patient information: Warfarin (Coumadin®)").
Uterine growths — When adult women experience menorrhagia, it is often due to a benign growth in the uterus. The most common growths are: Polyps, which are small grape-like growths of the lining of the uterus. Fibroids or leiomyomas, which are benign tumors involving the muscular walls of the uterus (myometrium) Adenomyosis, which refers to the growth of endometrial-like tissue within the muscular walls of the uterus
Rarely, cancer of the endometrium or myometrium can cause menorrhagia.
SIGNS AND SYMPTOMS — Women with menorrhagia typically have one or more of the following: Need to change pads/tampons more frequently than every three hours or use more than 21 pads/tampons during a period Need to use both pads and tampons to absorb menstrual flow Need to change pads or tampons during the night to absorb menstrual flow Pass blood clots larger than 1 inch Iron-deficiency anemia
DIAGNOSIS — If a healthcare provider suspects menorrhagia based on the woman's description of her bleeding, he or she will try to determine the cause by performing a medical history and physical examination. The physical examination is done to look for signs of bleeding elsewhere in the body, which could indicate a bleeding disorder. A pelvic examination will be done to determine the size and shape of the uterus. In women with fibroids, the uterus is often enlarged or irregularly shaped. An endometrial biopsy, in which a small sample of the uterine lining is removed, may be recommended in certain situations.
Laboratory tests may be recommended to look for bleeding disorders or thyroid disease. In some cases, the provider may recommend imaging tests, most commonly a pelvic ultrasound, to look for endometrial polyps, fibroids, or adenomyosis.
MEDICAL TREATMENT — The treatment of menorrhagia depends upon the cause and severity of the condition, the patient's preferences, the need to prevent pregnancy currently, and the woman's desire to have children in the future. Providers generally recommend that women with menorrhagia first try medical treatment (using medications). If one or more medical treatments are not successful, a surgical treatment may be recommended.
Combined oral contraceptives — Use of combined (estrogen and progesterone) oral contraceptives decreases menstrual blood loss over time. Alternatively, contraceptive patches or rings may be used instead of pills. All of these methods also help to prevent pregnancy. Combined oral contraceptives need to be taken daily.
Continuous dosing — Pills may be taken so that the woman has a period once per month or once every three to four months (called continuous dosing). This regimen is a particularly good treatment for women with painful periods. In this regimen, the woman takes the first three weeks of a pill pack, then immediately starts a new pack (without a break); the last week of (placebo) pills is not used. This can be continued for as long as desired.
Seasonale® is an extended cycle oral contraceptive product in which an active pill is taken every day for 12 weeks, followed by seven days of inactive (placebo) pills. Seasonique® is also an extended cycle oral contraceptive, although it contains seven days of a low dose estrogen pills instead of the placebo pills; this is intended to reduce breakthrough bleeding and estrogen withdrawal symptoms.
Taking an oral contraceptive for an extended time results in fewer periods per year, although many women experience breakthrough bleeding when starting this regimen. Breakthrough bleeding is inconvenient, but does not mean that there is an increased risk of pregnancy (unless pills are forgotten). (See "Patient information: Hormonal methods of birth control").
Progesterone — Progesterone is a hormone made by the ovary that is effective in preventing excessive bleeding in women with chronic anovulation. A synthetic form of progesterone, called progestin, can be given as a pill, injection, implant under the skin, or an intrauterine contraceptive. Progestin pills do not prevent pregnancy while the injection, implant, and intrauterine contraceptive do prevent pregnancy.
Pills — Progestin pills are usually taken for 11 to 14 days each month; within two weeks of the last pill, most women will begin to have a withdrawl bleed. Pills may be recommended every one to three months and help to prevent the uterine lining from becoming overly thickened, which can cause excessive bleeding. Progestin pills do not prevent pregnancy and are not useful for menorrhagia caused by adenomyosis, polyps, or fibroids.
Injection — Medroxyprogesterone acetate (Depo-Provera®) is a long-acting progestin that is injected deep into a muscle, such as the buttock or upper arm, once every three months. A similar preparation can be given subcutaneously (under the skin). Depo-Provera can reduce bleeding in women with menorrhagia, and it also is a very effective form of birth control; it prevents pregnancy for at least 12 weeks per dose. Because it is long-acting, it may not be ideal for women who wish to become pregnant shortly after stopping the medication. Although most women are able to conceive within 10 months, fertility may not return for up to 18 months after the last injection.
The most common side effects of Depo-Provera are irregular or prolonged bleeding and spotting, particularly during the first few months of use. Up to 50 percent of women completely stop having menstrual periods (amenorrhea) after one year of use. Menses generally return within six months of the last injection. Depo-Provera can cause weight gain and thinning of the bones in some women.
Intrauterine contraceptive — An intrauterine contraceptive (IUC) is a device that is made of molded plastic and coated with progestin (show picture 1). The IUC is inserted into a woman's uterus by a healthcare provider. A thin plastic string is attached to the device and can be felt inside the vagina. In the United States, the progestin-releasing IUC is called Mirena®. It is effective in reducing bleeding and preventing pregnancy for up to five years. The IUC is different than an intrauterine device (IUD), which is often coated with copper and causes heavier menstrual bleeding.
In one study, the Mirena reduced menstrual blood loss by as much as 97 percent after a year of use [1]. The most bothersome side effect was spotting during the first three months after the IUC was inserted; by six months, the majority of women had no bleeding or infrequent light bleeding. The progesterone releasing IUC is the most effective medical treatment for menorrhagia, is relatively inexpensive, and helps at least 60 percent of women to avoid surgical treatments for menorrhagia.
Implant — A single-rod progestin implant, Implanon®, has been approved for use in the US and elsewhere. A healthcare provider inserts it under the skin in the upper inner arm (show picture 2). It prevents pregnancy and can control bleeding for up to three years. However, the implant can be removed sooner if pregnancy is desired. Insertion and removal can be done in an office or clinic. It is effective within 24 hours of insertion. Irregular bleeding is the most bothersome side effect. Fertility returns rapidly after removal of the rod.
Nonsteroidal anti-inflammatory drugs (NSAIDs) — Nonsteroidal anti-inflammatory drugs, such as ibuprofen (Motrin® and Advil®) and mefenamic acid (Ponstel®), can help relieve the pain of menstrual cramping and reduce blood flow. NSAIDs are relatively inexpensive, have few side effects, and only need to be taken for three to five days during the menstrual period. However, some women find that NSAIDs cause stomach upset.
Gonadotropin-releasing hormone (GnRH) agonists — GnRH agonists may be used to temporarily control bleeding in women who are waiting to have a surgical treatment. Gonadotropin releasing hormone (GnRH) agonists (eg, nafarelin, leuprolide, goserelin) work by turning off ovarian production of estrogen, thereby causing a temporary type of menopause. The lack of estrogen causes the lining of the uterus to shrink and reduces pain in over 80 percent of patients. The drugs may be given as a nasal spray, implant, or injection.
The full dose of a GnRH agonist is usually taken for up to six months; they are not usually taken for longer due to the risk of bone thinning. Side effects of GnRH agonists include headaches in 20 percent of women, especially in patients with a history of migraine, and the signs and symptoms of menopause: lack of menstrual bleeding, hot flashes, vaginal dryness, decreased libido, insomnia, and loss of bone density (on average a 2 to 7 percent loss). Bone strength recovers substantially after the drug is stopped.
Many of these side effects can be minimized by giving estrogen or a bone strengthening drug along with the GnRH agonist. This treatment is not a permanent solution because heavy bleeding usually resumes when the drug is stopped.
Antifibrinolytic agents — Drugs like tranexamic acid and aminocaproic acid only need to be taken on the days of menses, do not interfere with fertility, and, since they act within two to three hours of administration, can also be used for acute control of bleeding. However, some women experience side effects, such as stomach problems, leg cramps, dizziness, and headaches, when they take these medications.
Danazol — Danazol is a medication that increases the level of androgens (male type hormone) and decreases the level of estrogen. This temporarily stops the menstrual period by inhibiting ovulation and ovarian production of estrogen and by shrinking the endometrium.
The medication is taken by mouth at a dose of 200 to 400 mg two to four times per day for 6 months or more. However, there is a high (75 percent) incidence of one or more side effects. Side effects may include weight gain, edema, decreased breast size, acne, oily skin, hirsutism (male pattern hair growth), deepening of the voice, headache, hot flashes, changes in libido, and mood changes. All of these changes are reversible, except for voice changes; however, a return to normal may take many months.
Danazol should not be taken by women with certain types of liver, kidney, and heart disease because these disorders may worsen. Women who could become pregnant must use a nonhormonal form of birth control (eg, condoms) while taking danazol because of a serious risk of birth defects if danazol is taken during pregnancy. (See "Patient information: Barrier methods of birth control").
SURGICAL TREATMENT — For women who have known abnormalities of the uterus that are known to cause menorrhagia, such as polyps or fibroids, surgical removal of these lesions often cures the menorrhagia. Some fibroids may also be treated by cutting off their blood supply. This procedure is called uterine artery embolization, and is discussed in depth in a separate topic review. (See "Patient information: Fibroids").
The two major surgical treatments for menorrhagia are:
Endometrial ablation — In this procedure, a physician destroys or removes most of the lining of the uterus. There are several methods of endometrial ablation, all of which use an instrument that is inserted through the cervix and into the uterine cavity. The procedure is usually done in a day surgery or office setting. To reduce pain, a sedative medication is given and local anesthesia is injected into the cervix. The most common postoperative side effects are cramping, vaginal discharge, and nausea. A pinkish vaginal discharge is present for two to three days after the procedure; this gradually becomes clear and watery discharge that lasts for two to 10 days. Uterine cramping may persist for 24 to 72 hours. Most women can resume their normal activities within a short time.
Endometrial ablation reduces and often eliminates menstrual blood flow in women with menorrhagia. However, it is not an option for women who may want to become pregnant in the future because the damage to the endometrium often prevents pregnancy.
A second endometrial ablation may be needed if symptoms persist or recur; between 5 and 20 percent of women who have this procedure have a second endometrial ablation to control uterine bleeding within three to five years of the initial procedure. In addition, 9 to 15 percent undergo a hysterectomy for persistent or new uterine symptoms.
Hysterectomy — Hysterectomy is surgical removal of the uterus. This is a permanent and complete treatment of menorrhagia since the source of bleeding (the uterus) is completely removed. However, hysterectomy is a major surgical procedure that has more complications and a longer recovery period than endometrial ablation. Pregnancy is not possible after hysterectomy. (See "Patient information: Abdominal hysterectomy" and see "Patient information: Vaginal hysterectomy").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Women's Health Information Center
(www.4women.gov)
The Mayo Clinic
(www.mayoclinic.com)
[2-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Andersson, JK, Rybo, G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 1990; 97:690.
2. Warner, PE, Critchley, HO, Lumsden, MA, et al. Menorrhagia I: Measured blood loss, clinical features, and outcome in women with heavy periods: A survey with follow-up data. Am J Obstet Gynecol 2004; 190:1216.
3. Iyer, V, Farquhar, C, Jepson, R. Oral contraceptive pills for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; :CD000154.
4. Lethaby, AE, Cooke, I, Rees, M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005; :CD002126.
5. Marjoribanks, J, Lethaby, A, Farquhar, C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev 2003; :CD003855.
Menorrhagia (excessive menstrual bleeding)
INTRODUCTION — In a normal menstrual cycle, the average woman loses about 2 to 3 tablespoons (35 to 40 milliliters) of blood. However, some women lose much larger amounts of blood. Menorrhagia is the medical term for excessive or prolonged menstrual bleeding.
Women who lose 5 to 6 tablespoons (about 80 milliliters) of blood or more during their menstrual period are said to have menorrhagia. Losing a lot of blood during the menstrual period can cause medical problems and lifestyle issues. As an example, more than 50 percent of women with menorrhagia develop iron deficiency anemia (lower than normal amounts of red blood cells). Extremely heavy bleeding may interfere with a woman's life because of the frequent need to change pads or tampons and because heavy bleeding can cause painful menstrual cramps.
THE NORMAL MENSTRUAL CYCLE — Most women's menstrual cycle lasts between 24 and 35 days; the average is 28 days. During this time, the uterus, ovaries, hypothalamus, and pituitary gland follow a sequence of events that prepares the body for pregnancy. Two hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), are made by the pituitary gland. These hormones stimulate the ovary to make two other hormones, progesterone and estrogen.
During the first half of the cycle, FSH stimulates a follicle to develop in one of the ovaries. This causes the estrogen level to rise, causing the lining of the uterus to grow and thicken (show figure 1). These events stimulate a risk in the LH level, which ultimately causes the follicle to release an egg from the ovary (called ovulation).
After ovulation, the ovary produces both estrogen and progesterone, which prepare the uterus for possible implantation and pregnancy. Progesterone also helps to "stabilize" the lining of the uterus, preventing abnormal bleeding. If pregnancy does not occur, estrogen and progesterone levels drop and the lining of the uterus is shed. The process of shedding is called the menstrual period. The menstrual blood contains blood as well as tissue from inside the uterus. Most women lose 2 to 3 tablespoons of blood over 3 to 7 days.
CAUSES — In women with menorrhagia, the sequence of events that leads to the menstrual period may be normal but bleeding is excessive because of an abnormal uterus (eg, due to abnormal growths) or because of a problem with blood clotting. In other women with menorrhagia, this sequence of events is abnormal because ovulation does not occur.
Anovulation — Anovulation occurs when a woman's ovaries fail to produce and release an egg (ovulate) once per month. Since the normal hormonal changes of ovulation do not occur, the lining of the uterus (called the endometrium) does not uniformly shed and regrow as in a normal menstrual cycle. Instead, excessive estrogen stimulates the lining of the uterus (endometrium) to continue growing and become thicker. Progesterone is not present at the usual levels, which causes the lining to shed irregularly, which results in heavy and/or prolonged bleeding.
Menorrhagia in adolescents is usually caused by anovulation. Anovulatory bleeding is also common before menopause (called perimenopause) and with some endocrine disorders, such as hypothyroidism and polycystic ovary syndrome. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Bleeding tendency — Menorrhagia can result from conditions that prevent the blood from clotting normally. Some examples are von Willebrand disease, low platelet count or platelet dysfunction, and use of anticoagulants ("blood thinners") such as warfarin. (See "Patient information: Warfarin (Coumadin®)").
Uterine growths — When adult women experience menorrhagia, it is often due to a benign growth in the uterus. The most common growths are: Polyps, which are small grape-like growths of the lining of the uterus. Fibroids or leiomyomas, which are benign tumors involving the muscular walls of the uterus (myometrium) Adenomyosis, which refers to the growth of endometrial-like tissue within the muscular walls of the uterus
Rarely, cancer of the endometrium or myometrium can cause menorrhagia.
SIGNS AND SYMPTOMS — Women with menorrhagia typically have one or more of the following: Need to change pads/tampons more frequently than every three hours or use more than 21 pads/tampons during a period Need to use both pads and tampons to absorb menstrual flow Need to change pads or tampons during the night to absorb menstrual flow Pass blood clots larger than 1 inch Iron-deficiency anemia
DIAGNOSIS — If a healthcare provider suspects menorrhagia based on the woman's description of her bleeding, he or she will try to determine the cause by performing a medical history and physical examination. The physical examination is done to look for signs of bleeding elsewhere in the body, which could indicate a bleeding disorder. A pelvic examination will be done to determine the size and shape of the uterus. In women with fibroids, the uterus is often enlarged or irregularly shaped. An endometrial biopsy, in which a small sample of the uterine lining is removed, may be recommended in certain situations.
Laboratory tests may be recommended to look for bleeding disorders or thyroid disease. In some cases, the provider may recommend imaging tests, most commonly a pelvic ultrasound, to look for endometrial polyps, fibroids, or adenomyosis.
MEDICAL TREATMENT — The treatment of menorrhagia depends upon the cause and severity of the condition, the patient's preferences, the need to prevent pregnancy currently, and the woman's desire to have children in the future. Providers generally recommend that women with menorrhagia first try medical treatment (using medications). If one or more medical treatments are not successful, a surgical treatment may be recommended.
Combined oral contraceptives — Use of combined (estrogen and progesterone) oral contraceptives decreases menstrual blood loss over time. Alternatively, contraceptive patches or rings may be used instead of pills. All of these methods also help to prevent pregnancy. Combined oral contraceptives need to be taken daily.
Continuous dosing — Pills may be taken so that the woman has a period once per month or once every three to four months (called continuous dosing). This regimen is a particularly good treatment for women with painful periods. In this regimen, the woman takes the first three weeks of a pill pack, then immediately starts a new pack (without a break); the last week of (placebo) pills is not used. This can be continued for as long as desired.
Seasonale® is an extended cycle oral contraceptive product in which an active pill is taken every day for 12 weeks, followed by seven days of inactive (placebo) pills. Seasonique® is also an extended cycle oral contraceptive, although it contains seven days of a low dose estrogen pills instead of the placebo pills; this is intended to reduce breakthrough bleeding and estrogen withdrawal symptoms.
Taking an oral contraceptive for an extended time results in fewer periods per year, although many women experience breakthrough bleeding when starting this regimen. Breakthrough bleeding is inconvenient, but does not mean that there is an increased risk of pregnancy (unless pills are forgotten). (See "Patient information: Hormonal methods of birth control").
Progesterone — Progesterone is a hormone made by the ovary that is effective in preventing excessive bleeding in women with chronic anovulation. A synthetic form of progesterone, called progestin, can be given as a pill, injection, implant under the skin, or an intrauterine contraceptive. Progestin pills do not prevent pregnancy while the injection, implant, and intrauterine contraceptive do prevent pregnancy.
Pills — Progestin pills are usually taken for 11 to 14 days each month; within two weeks of the last pill, most women will begin to have a withdrawl bleed. Pills may be recommended every one to three months and help to prevent the uterine lining from becoming overly thickened, which can cause excessive bleeding. Progestin pills do not prevent pregnancy and are not useful for menorrhagia caused by adenomyosis, polyps, or fibroids.
Injection — Medroxyprogesterone acetate (Depo-Provera®) is a long-acting progestin that is injected deep into a muscle, such as the buttock or upper arm, once every three months. A similar preparation can be given subcutaneously (under the skin). Depo-Provera can reduce bleeding in women with menorrhagia, and it also is a very effective form of birth control; it prevents pregnancy for at least 12 weeks per dose. Because it is long-acting, it may not be ideal for women who wish to become pregnant shortly after stopping the medication. Although most women are able to conceive within 10 months, fertility may not return for up to 18 months after the last injection.
The most common side effects of Depo-Provera are irregular or prolonged bleeding and spotting, particularly during the first few months of use. Up to 50 percent of women completely stop having menstrual periods (amenorrhea) after one year of use. Menses generally return within six months of the last injection. Depo-Provera can cause weight gain and thinning of the bones in some women.
Intrauterine contraceptive — An intrauterine contraceptive (IUC) is a device that is made of molded plastic and coated with progestin (show picture 1). The IUC is inserted into a woman's uterus by a healthcare provider. A thin plastic string is attached to the device and can be felt inside the vagina. In the United States, the progestin-releasing IUC is called Mirena®. It is effective in reducing bleeding and preventing pregnancy for up to five years. The IUC is different than an intrauterine device (IUD), which is often coated with copper and causes heavier menstrual bleeding.
In one study, the Mirena reduced menstrual blood loss by as much as 97 percent after a year of use [1]. The most bothersome side effect was spotting during the first three months after the IUC was inserted; by six months, the majority of women had no bleeding or infrequent light bleeding. The progesterone releasing IUC is the most effective medical treatment for menorrhagia, is relatively inexpensive, and helps at least 60 percent of women to avoid surgical treatments for menorrhagia.
Implant — A single-rod progestin implant, Implanon®, has been approved for use in the US and elsewhere. A healthcare provider inserts it under the skin in the upper inner arm (show picture 2). It prevents pregnancy and can control bleeding for up to three years. However, the implant can be removed sooner if pregnancy is desired. Insertion and removal can be done in an office or clinic. It is effective within 24 hours of insertion. Irregular bleeding is the most bothersome side effect. Fertility returns rapidly after removal of the rod.
Nonsteroidal anti-inflammatory drugs (NSAIDs) — Nonsteroidal anti-inflammatory drugs, such as ibuprofen (Motrin® and Advil®) and mefenamic acid (Ponstel®), can help relieve the pain of menstrual cramping and reduce blood flow. NSAIDs are relatively inexpensive, have few side effects, and only need to be taken for three to five days during the menstrual period. However, some women find that NSAIDs cause stomach upset.
Gonadotropin-releasing hormone (GnRH) agonists — GnRH agonists may be used to temporarily control bleeding in women who are waiting to have a surgical treatment. Gonadotropin releasing hormone (GnRH) agonists (eg, nafarelin, leuprolide, goserelin) work by turning off ovarian production of estrogen, thereby causing a temporary type of menopause. The lack of estrogen causes the lining of the uterus to shrink and reduces pain in over 80 percent of patients. The drugs may be given as a nasal spray, implant, or injection.
The full dose of a GnRH agonist is usually taken for up to six months; they are not usually taken for longer due to the risk of bone thinning. Side effects of GnRH agonists include headaches in 20 percent of women, especially in patients with a history of migraine, and the signs and symptoms of menopause: lack of menstrual bleeding, hot flashes, vaginal dryness, decreased libido, insomnia, and loss of bone density (on average a 2 to 7 percent loss). Bone strength recovers substantially after the drug is stopped.
Many of these side effects can be minimized by giving estrogen or a bone strengthening drug along with the GnRH agonist. This treatment is not a permanent solution because heavy bleeding usually resumes when the drug is stopped.
Antifibrinolytic agents — Drugs like tranexamic acid and aminocaproic acid only need to be taken on the days of menses, do not interfere with fertility, and, since they act within two to three hours of administration, can also be used for acute control of bleeding. However, some women experience side effects, such as stomach problems, leg cramps, dizziness, and headaches, when they take these medications.
Danazol — Danazol is a medication that increases the level of androgens (male type hormone) and decreases the level of estrogen. This temporarily stops the menstrual period by inhibiting ovulation and ovarian production of estrogen and by shrinking the endometrium.
The medication is taken by mouth at a dose of 200 to 400 mg two to four times per day for 6 months or more. However, there is a high (75 percent) incidence of one or more side effects. Side effects may include weight gain, edema, decreased breast size, acne, oily skin, hirsutism (male pattern hair growth), deepening of the voice, headache, hot flashes, changes in libido, and mood changes. All of these changes are reversible, except for voice changes; however, a return to normal may take many months.
Danazol should not be taken by women with certain types of liver, kidney, and heart disease because these disorders may worsen. Women who could become pregnant must use a nonhormonal form of birth control (eg, condoms) while taking danazol because of a serious risk of birth defects if danazol is taken during pregnancy. (See "Patient information: Barrier methods of birth control").
SURGICAL TREATMENT — For women who have known abnormalities of the uterus that are known to cause menorrhagia, such as polyps or fibroids, surgical removal of these lesions often cures the menorrhagia. Some fibroids may also be treated by cutting off their blood supply. This procedure is called uterine artery embolization, and is discussed in depth in a separate topic review. (See "Patient information: Fibroids").
The two major surgical treatments for menorrhagia are:
Endometrial ablation — In this procedure, a physician destroys or removes most of the lining of the uterus. There are several methods of endometrial ablation, all of which use an instrument that is inserted through the cervix and into the uterine cavity. The procedure is usually done in a day surgery or office setting. To reduce pain, a sedative medication is given and local anesthesia is injected into the cervix. The most common postoperative side effects are cramping, vaginal discharge, and nausea. A pinkish vaginal discharge is present for two to three days after the procedure; this gradually becomes clear and watery discharge that lasts for two to 10 days. Uterine cramping may persist for 24 to 72 hours. Most women can resume their normal activities within a short time.
Endometrial ablation reduces and often eliminates menstrual blood flow in women with menorrhagia. However, it is not an option for women who may want to become pregnant in the future because the damage to the endometrium often prevents pregnancy.
A second endometrial ablation may be needed if symptoms persist or recur; between 5 and 20 percent of women who have this procedure have a second endometrial ablation to control uterine bleeding within three to five years of the initial procedure. In addition, 9 to 15 percent undergo a hysterectomy for persistent or new uterine symptoms.
Hysterectomy — Hysterectomy is surgical removal of the uterus. This is a permanent and complete treatment of menorrhagia since the source of bleeding (the uterus) is completely removed. However, hysterectomy is a major surgical procedure that has more complications and a longer recovery period than endometrial ablation. Pregnancy is not possible after hysterectomy. (See "Patient information: Abdominal hysterectomy" and see "Patient information: Vaginal hysterectomy").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Women's Health Information Center
(www.4women.gov)
The Mayo Clinic
(www.mayoclinic.com)
[2-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Andersson, JK, Rybo, G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 1990; 97:690.
2. Warner, PE, Critchley, HO, Lumsden, MA, et al. Menorrhagia I: Measured blood loss, clinical features, and outcome in women with heavy periods: A survey with follow-up data. Am J Obstet Gynecol 2004; 190:1216.
3. Iyer, V, Farquhar, C, Jepson, R. Oral contraceptive pills for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; :CD000154.
4. Lethaby, AE, Cooke, I, Rees, M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005; :CD002126.
5. Marjoribanks, J, Lethaby, A, Farquhar, C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev 2003; :CD003855.
Women who lose 5 to 6 tablespoons (about 80 milliliters) of blood or more during their menstrual period are said to have menorrhagia. Losing a lot of blood during the menstrual period can cause medical problems and lifestyle issues. As an example, more than 50 percent of women with menorrhagia develop iron deficiency anemia (lower than normal amounts of red blood cells). Extremely heavy bleeding may interfere with a woman's life because of the frequent need to change pads or tampons and because heavy bleeding can cause painful menstrual cramps.
THE NORMAL MENSTRUAL CYCLE — Most women's menstrual cycle lasts between 24 and 35 days; the average is 28 days. During this time, the uterus, ovaries, hypothalamus, and pituitary gland follow a sequence of events that prepares the body for pregnancy. Two hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), are made by the pituitary gland. These hormones stimulate the ovary to make two other hormones, progesterone and estrogen.
During the first half of the cycle, FSH stimulates a follicle to develop in one of the ovaries. This causes the estrogen level to rise, causing the lining of the uterus to grow and thicken (show figure 1). These events stimulate a risk in the LH level, which ultimately causes the follicle to release an egg from the ovary (called ovulation).
After ovulation, the ovary produces both estrogen and progesterone, which prepare the uterus for possible implantation and pregnancy. Progesterone also helps to "stabilize" the lining of the uterus, preventing abnormal bleeding. If pregnancy does not occur, estrogen and progesterone levels drop and the lining of the uterus is shed. The process of shedding is called the menstrual period. The menstrual blood contains blood as well as tissue from inside the uterus. Most women lose 2 to 3 tablespoons of blood over 3 to 7 days.
CAUSES — In women with menorrhagia, the sequence of events that leads to the menstrual period may be normal but bleeding is excessive because of an abnormal uterus (eg, due to abnormal growths) or because of a problem with blood clotting. In other women with menorrhagia, this sequence of events is abnormal because ovulation does not occur.
Anovulation — Anovulation occurs when a woman's ovaries fail to produce and release an egg (ovulate) once per month. Since the normal hormonal changes of ovulation do not occur, the lining of the uterus (called the endometrium) does not uniformly shed and regrow as in a normal menstrual cycle. Instead, excessive estrogen stimulates the lining of the uterus (endometrium) to continue growing and become thicker. Progesterone is not present at the usual levels, which causes the lining to shed irregularly, which results in heavy and/or prolonged bleeding.
Menorrhagia in adolescents is usually caused by anovulation. Anovulatory bleeding is also common before menopause (called perimenopause) and with some endocrine disorders, such as hypothyroidism and polycystic ovary syndrome. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Bleeding tendency — Menorrhagia can result from conditions that prevent the blood from clotting normally. Some examples are von Willebrand disease, low platelet count or platelet dysfunction, and use of anticoagulants ("blood thinners") such as warfarin. (See "Patient information: Warfarin (Coumadin®)").
Uterine growths — When adult women experience menorrhagia, it is often due to a benign growth in the uterus. The most common growths are: Polyps, which are small grape-like growths of the lining of the uterus. Fibroids or leiomyomas, which are benign tumors involving the muscular walls of the uterus (myometrium) Adenomyosis, which refers to the growth of endometrial-like tissue within the muscular walls of the uterus
Rarely, cancer of the endometrium or myometrium can cause menorrhagia.
SIGNS AND SYMPTOMS — Women with menorrhagia typically have one or more of the following: Need to change pads/tampons more frequently than every three hours or use more than 21 pads/tampons during a period Need to use both pads and tampons to absorb menstrual flow Need to change pads or tampons during the night to absorb menstrual flow Pass blood clots larger than 1 inch Iron-deficiency anemia
DIAGNOSIS — If a healthcare provider suspects menorrhagia based on the woman's description of her bleeding, he or she will try to determine the cause by performing a medical history and physical examination. The physical examination is done to look for signs of bleeding elsewhere in the body, which could indicate a bleeding disorder. A pelvic examination will be done to determine the size and shape of the uterus. In women with fibroids, the uterus is often enlarged or irregularly shaped. An endometrial biopsy, in which a small sample of the uterine lining is removed, may be recommended in certain situations.
Laboratory tests may be recommended to look for bleeding disorders or thyroid disease. In some cases, the provider may recommend imaging tests, most commonly a pelvic ultrasound, to look for endometrial polyps, fibroids, or adenomyosis.
MEDICAL TREATMENT — The treatment of menorrhagia depends upon the cause and severity of the condition, the patient's preferences, the need to prevent pregnancy currently, and the woman's desire to have children in the future. Providers generally recommend that women with menorrhagia first try medical treatment (using medications). If one or more medical treatments are not successful, a surgical treatment may be recommended.
Combined oral contraceptives — Use of combined (estrogen and progesterone) oral contraceptives decreases menstrual blood loss over time. Alternatively, contraceptive patches or rings may be used instead of pills. All of these methods also help to prevent pregnancy. Combined oral contraceptives need to be taken daily.
Continuous dosing — Pills may be taken so that the woman has a period once per month or once every three to four months (called continuous dosing). This regimen is a particularly good treatment for women with painful periods. In this regimen, the woman takes the first three weeks of a pill pack, then immediately starts a new pack (without a break); the last week of (placebo) pills is not used. This can be continued for as long as desired.
Seasonale® is an extended cycle oral contraceptive product in which an active pill is taken every day for 12 weeks, followed by seven days of inactive (placebo) pills. Seasonique® is also an extended cycle oral contraceptive, although it contains seven days of a low dose estrogen pills instead of the placebo pills; this is intended to reduce breakthrough bleeding and estrogen withdrawal symptoms.
Taking an oral contraceptive for an extended time results in fewer periods per year, although many women experience breakthrough bleeding when starting this regimen. Breakthrough bleeding is inconvenient, but does not mean that there is an increased risk of pregnancy (unless pills are forgotten). (See "Patient information: Hormonal methods of birth control").
Progesterone — Progesterone is a hormone made by the ovary that is effective in preventing excessive bleeding in women with chronic anovulation. A synthetic form of progesterone, called progestin, can be given as a pill, injection, implant under the skin, or an intrauterine contraceptive. Progestin pills do not prevent pregnancy while the injection, implant, and intrauterine contraceptive do prevent pregnancy.
Pills — Progestin pills are usually taken for 11 to 14 days each month; within two weeks of the last pill, most women will begin to have a withdrawl bleed. Pills may be recommended every one to three months and help to prevent the uterine lining from becoming overly thickened, which can cause excessive bleeding. Progestin pills do not prevent pregnancy and are not useful for menorrhagia caused by adenomyosis, polyps, or fibroids.
Injection — Medroxyprogesterone acetate (Depo-Provera®) is a long-acting progestin that is injected deep into a muscle, such as the buttock or upper arm, once every three months. A similar preparation can be given subcutaneously (under the skin). Depo-Provera can reduce bleeding in women with menorrhagia, and it also is a very effective form of birth control; it prevents pregnancy for at least 12 weeks per dose. Because it is long-acting, it may not be ideal for women who wish to become pregnant shortly after stopping the medication. Although most women are able to conceive within 10 months, fertility may not return for up to 18 months after the last injection.
The most common side effects of Depo-Provera are irregular or prolonged bleeding and spotting, particularly during the first few months of use. Up to 50 percent of women completely stop having menstrual periods (amenorrhea) after one year of use. Menses generally return within six months of the last injection. Depo-Provera can cause weight gain and thinning of the bones in some women.
Intrauterine contraceptive — An intrauterine contraceptive (IUC) is a device that is made of molded plastic and coated with progestin (show picture 1). The IUC is inserted into a woman's uterus by a healthcare provider. A thin plastic string is attached to the device and can be felt inside the vagina. In the United States, the progestin-releasing IUC is called Mirena®. It is effective in reducing bleeding and preventing pregnancy for up to five years. The IUC is different than an intrauterine device (IUD), which is often coated with copper and causes heavier menstrual bleeding.
In one study, the Mirena reduced menstrual blood loss by as much as 97 percent after a year of use [1]. The most bothersome side effect was spotting during the first three months after the IUC was inserted; by six months, the majority of women had no bleeding or infrequent light bleeding. The progesterone releasing IUC is the most effective medical treatment for menorrhagia, is relatively inexpensive, and helps at least 60 percent of women to avoid surgical treatments for menorrhagia.
Implant — A single-rod progestin implant, Implanon®, has been approved for use in the US and elsewhere. A healthcare provider inserts it under the skin in the upper inner arm (show picture 2). It prevents pregnancy and can control bleeding for up to three years. However, the implant can be removed sooner if pregnancy is desired. Insertion and removal can be done in an office or clinic. It is effective within 24 hours of insertion. Irregular bleeding is the most bothersome side effect. Fertility returns rapidly after removal of the rod.
Nonsteroidal anti-inflammatory drugs (NSAIDs) — Nonsteroidal anti-inflammatory drugs, such as ibuprofen (Motrin® and Advil®) and mefenamic acid (Ponstel®), can help relieve the pain of menstrual cramping and reduce blood flow. NSAIDs are relatively inexpensive, have few side effects, and only need to be taken for three to five days during the menstrual period. However, some women find that NSAIDs cause stomach upset.
Gonadotropin-releasing hormone (GnRH) agonists — GnRH agonists may be used to temporarily control bleeding in women who are waiting to have a surgical treatment. Gonadotropin releasing hormone (GnRH) agonists (eg, nafarelin, leuprolide, goserelin) work by turning off ovarian production of estrogen, thereby causing a temporary type of menopause. The lack of estrogen causes the lining of the uterus to shrink and reduces pain in over 80 percent of patients. The drugs may be given as a nasal spray, implant, or injection.
The full dose of a GnRH agonist is usually taken for up to six months; they are not usually taken for longer due to the risk of bone thinning. Side effects of GnRH agonists include headaches in 20 percent of women, especially in patients with a history of migraine, and the signs and symptoms of menopause: lack of menstrual bleeding, hot flashes, vaginal dryness, decreased libido, insomnia, and loss of bone density (on average a 2 to 7 percent loss). Bone strength recovers substantially after the drug is stopped.
Many of these side effects can be minimized by giving estrogen or a bone strengthening drug along with the GnRH agonist. This treatment is not a permanent solution because heavy bleeding usually resumes when the drug is stopped.
Antifibrinolytic agents — Drugs like tranexamic acid and aminocaproic acid only need to be taken on the days of menses, do not interfere with fertility, and, since they act within two to three hours of administration, can also be used for acute control of bleeding. However, some women experience side effects, such as stomach problems, leg cramps, dizziness, and headaches, when they take these medications.
Danazol — Danazol is a medication that increases the level of androgens (male type hormone) and decreases the level of estrogen. This temporarily stops the menstrual period by inhibiting ovulation and ovarian production of estrogen and by shrinking the endometrium.
The medication is taken by mouth at a dose of 200 to 400 mg two to four times per day for 6 months or more. However, there is a high (75 percent) incidence of one or more side effects. Side effects may include weight gain, edema, decreased breast size, acne, oily skin, hirsutism (male pattern hair growth), deepening of the voice, headache, hot flashes, changes in libido, and mood changes. All of these changes are reversible, except for voice changes; however, a return to normal may take many months.
Danazol should not be taken by women with certain types of liver, kidney, and heart disease because these disorders may worsen. Women who could become pregnant must use a nonhormonal form of birth control (eg, condoms) while taking danazol because of a serious risk of birth defects if danazol is taken during pregnancy. (See "Patient information: Barrier methods of birth control").
SURGICAL TREATMENT — For women who have known abnormalities of the uterus that are known to cause menorrhagia, such as polyps or fibroids, surgical removal of these lesions often cures the menorrhagia. Some fibroids may also be treated by cutting off their blood supply. This procedure is called uterine artery embolization, and is discussed in depth in a separate topic review. (See "Patient information: Fibroids").
The two major surgical treatments for menorrhagia are:
Endometrial ablation — In this procedure, a physician destroys or removes most of the lining of the uterus. There are several methods of endometrial ablation, all of which use an instrument that is inserted through the cervix and into the uterine cavity. The procedure is usually done in a day surgery or office setting. To reduce pain, a sedative medication is given and local anesthesia is injected into the cervix. The most common postoperative side effects are cramping, vaginal discharge, and nausea. A pinkish vaginal discharge is present for two to three days after the procedure; this gradually becomes clear and watery discharge that lasts for two to 10 days. Uterine cramping may persist for 24 to 72 hours. Most women can resume their normal activities within a short time.
Endometrial ablation reduces and often eliminates menstrual blood flow in women with menorrhagia. However, it is not an option for women who may want to become pregnant in the future because the damage to the endometrium often prevents pregnancy.
A second endometrial ablation may be needed if symptoms persist or recur; between 5 and 20 percent of women who have this procedure have a second endometrial ablation to control uterine bleeding within three to five years of the initial procedure. In addition, 9 to 15 percent undergo a hysterectomy for persistent or new uterine symptoms.
Hysterectomy — Hysterectomy is surgical removal of the uterus. This is a permanent and complete treatment of menorrhagia since the source of bleeding (the uterus) is completely removed. However, hysterectomy is a major surgical procedure that has more complications and a longer recovery period than endometrial ablation. Pregnancy is not possible after hysterectomy. (See "Patient information: Abdominal hysterectomy" and see "Patient information: Vaginal hysterectomy").
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Women's Health Information Center
(www.4women.gov)
The Mayo Clinic
(www.mayoclinic.com)
[2-5]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Andersson, JK, Rybo, G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 1990; 97:690.
2. Warner, PE, Critchley, HO, Lumsden, MA, et al. Menorrhagia I: Measured blood loss, clinical features, and outcome in women with heavy periods: A survey with follow-up data. Am J Obstet Gynecol 2004; 190:1216.
3. Iyer, V, Farquhar, C, Jepson, R. Oral contraceptive pills for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; :CD000154.
4. Lethaby, AE, Cooke, I, Rees, M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2005; :CD002126.
5. Marjoribanks, J, Lethaby, A, Farquhar, C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev 2003; :CD003855.
Abnormal uterine bleeding
INTRODUCTION — Under normal circumstances, a woman's uterus sheds a limited amount of blood during each menstrual period. Bleeding that occurs between menstrual periods or excessive bleeding that occurs during menstruation is considered to be abnormal uterine bleeding. Once a woman enters menopause and menstrual cycles have ended, any bleeding, other than the small amounts that can occur in women on hormone replacement therapy, is considered abnormal.
Abnormal uterine bleeding can be caused by many different conditions. A history and physical examination are important first steps in determining the cause.
CAUSES — While most conditions that cause abnormal uterine bleeding can occur at any age, some are more likely to occur at particular times in a woman's life.
Bleeding before menarche — Bleeding before menarche (the first period in a girl's life) is always abnormal and can be caused by trauma, a foreign body (such as toys, coins, or toilet tissue), irritation of the genital area (due to bubble bath, soaps, lotions, or infection), or urinary tract problems. Bleeding can also occur as a result of sexual abuse.
Adolescents — Many girls have episodes of irregular bleeding during the first few years after their periods begin. This usually resolves without treatment when the girl's hormonal cycle and ovulation normalizes. If bleeding persists beyond this time, or if the bleeding is heavy, further evaluation is needed.
Abnormal bleeding in this age group can also be caused by pregnancy, bleeding disorders, some medical illnesses, and infection.
Birth control pills — Girls and women who use oral contraceptives may experience "breakthrough" bleeding between periods. If this occurs during the first months of oral contraceptive use, it may be due to changes in the lining of the uterus. If it persists for more than several months, a different oral contraceptive may be prescribed.
Breakthrough bleeding can also happen if the oral contraceptive is not taken regularly. If this occurs, the breakthrough bleeding may be an indication that the pill is not effective. Additional contraception may be necessary until the oral contraceptives are taken on a regular schedule and the breakthrough bleeding stops. If an adolescent has persistent breakthrough bleeding, further evaluation is needed.
Premenopausal women — Many different conditions can cause abnormal bleeding in women between adolescence and menopause. Abrupt changes in hormone levels at the time of expected ovulation can cause vaginal spotting, or small amounts of bleeding. As noted above, breakthrough bleeding can occur in women who use oral contraceptives.
In women who do not ovulate regularly (anovulatory women), irregular changes in hormone levels can cause bleeding to occur intermittently and in varying amounts. Although anovulation is most common when periods first begin and during perimenopause, it can occur at any time during the reproductive years. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Among women who ovulate normally, some experience excessive blood loss during their periods or bleed between periods. The most common causes of such bleeding are uterine fibroids or polyps. These irregular growths and benign tumors are composed of uterine tissue that distort the structure of the uterus and lead to abnormal uterine bleeding. Fibroids and polyps can also occur in anovulatory women. (See "Patient information: Fibroids" and see "Patient information: Menorrhagia (Excessive menstrual bleeding)").
Other causes of abnormal uterine bleeding in premenopausal women include: Pregnancy Cancer of the endometrium (lining of the uterus) or benign precancerous endometrial lesions Endometritis or inflammation of the endometrium A pelvic or vaginal infection Clotting disorders such as von Willebrand disease, platelet abnormalities, or problems with clotting factors Some systemic illnesses such as hypothyroidism, liver disease, or chronic renal disease
Perimenopausal women — Before menstruation stops, a woman passes through a period called perimenopause. During perimenopause, normal hormonal cycling begins to change and ovulation may be inconsistent. While estrogen secretion continues, progesterone secretion declines. These hormonal changes can cause the endometrium to grow and produce excess tissue, increasing the chances that polyps or endometrial hyperplasia (thickened lining of the uterus) will develop and potentially cause abnormal bleeding. Women in perimenopause are also at risk for other conditions that cause abnormal bleeding, including cancer, infection, and systemic illnesses. Further evaluation is indicated if a woman experiences persistent irregular menstrual cycles or an episode of profuse bleeding.
Women in perimenopause still ovulate some of the time and can become pregnant; pregnancy can cause abnormal bleeding. In addition, women in perimenopause may use hormonal contraceptive medications, which can cause breakthrough bleeding.
Menopausal women — A number of conditions can cause abnormal bleeding during the menopause. Many women are on hormone replacement therapy at some point during menopause and may experience cyclical bleeding. Any other bleeding that occurs during menopause is abnormal and should be investigated. Causes of abnormal bleeding during menopause include: Atrophy or thinning of the tissue lining the vagina and uterus Cancer of the uterine lining or endometrium Polyps or fibroids Endometrial hyperplasia Infection of the uterus Use of blood thinners or anticoagulants Side effects of radiation therapy
EVALUATION
Initial assessment — While taking a woman's medical history, a clinician will review a number of factors that can help identify the cause of abnormal bleeding. These include: the duration and quantity of the bleeding; factors that seem to bring the bleeding on; symptoms that occur along with the bleeding such as pain, fever, or vaginal odor; the relationship between bleeding and sexual relations; whether there is a personal or family history of bleeding disorders; the woman's medical history and medications she is taking; and whether the woman has experienced a weight change, stress, started a new exercise program, or has any underlying medical problems.
The clinician will perform a general physical exam to evaluate the woman's overall health, and a pelvic examination to confirm that the bleeding is from the uterus and not from another site like the external genitals or the rectum. During the pelvic exam, the clinician will look for any obvious lesions (cuts, sores, or tumors) and will examine the size and shape of the uterus. They will examine the cervix to look for signs of cervical bleeding, and a Pap smear may be obtained to examine the cells of the cervix (the lower end of the uterus, where it opens to the vagina).
In addition to a careful history and physical examination, laboratory tests and diagnostic procedures may be used to identify the cause of abnormal bleeding.
Lab tests — In premenopausal women, a pregnancy test is usually performed. If there is any abnormal vaginal discharge, a culture may be performed. Lab tests may also be conducted to determine whether there are problems with blood clotting or other systemic conditions, such as hypothyroidism, liver disease, or kidney problems.
Tests to determine ovulatory status — Because hormonal irregularities can contribute to abnormal uterine bleeding, blood tests may be performed in premenopausal women to determine whether they ovulate (produce an egg) during each monthly cycle. As an example, a woman may be asked to record when her periods begin and end for several months and to note any premenstrual changes, like cramps or breast tenderness, that occur. Progesterone, which is released at the time of ovulation, may be measured with a blood test.
Endometrial assessment — Tests that assess the endometrium (lining of the uterus) may be performed to rule out endometrial cancer and structural abnormalities such as uterine fibroids or polyps. Such tests include:
Endometrial biopsy — An endometrial biopsy is often performed in women over age 35 to rule out endometrial cancer or unusual endometrial growths. A biopsy may also be performed in women younger than 35 if they have risk factors for endometrial cancer. Risks include obesity, chronic anovulation, history of breast cancer, tamoxifen use or a family history of breast cancer or some other cancers. During the biopsy, a thin instrument is inserted through the vagina into the uterus to obtain a small sample of endometrial tissue. The biopsy can be performed in a healthcare provider's office without anesthesia. Because only a small portion of the endometrium is sampled, the biopsy may miss some causes of bleeding and other tests may be necessary.
Transvaginal ultrasound — An ultrasound uses sound waves to measure an organ's shape and structure. In a transvaginal ultrasound, a small ultrasound probe is inserted into the vagina so that it is closer to the uterus and can provide a cleare image of uterine contents. A transvaginal ultrasound is a minimally invasive way to determine whether abnormal uterine structures, or signs of excessive endometrial growth, are present. However, because it cannot distinguish between different types of structural abnormalities, further testing may be necessary if any are found.
Saline infusion sonography or sonohysterography — In this test, a transvaginal ultrasound is performed after sterile saline is instilled into the uterus. This procedure gives a better picture of the inside of the uterus, and small lesions can be more easily detected. However, because tissue samples cannot be obtained during the procedure, a final diagnosis is not always possible and additional evaluation through hysteroscopy or dilation and curettage (D&C) may be necessary.
Magnetic resonance imaging (MRI) — MRI is non-invasive and uses a magnetic field and radio waves to visualize organs. It is sometimes used to determine the presence of fibroids or other structural abnormalities.
Hysteroscopy — In a hysteroscopy, a small scope is inserted through the cervix and into the uterus. Air or fluid is injected to expand the uterus and to allow the physician to see the inside of the uterus. Tissue samples may be taken. Sedation with regional anesthesia (eg, spinal or epidural) or general anesthesia (medicine given to induce sleep) is used to minimize discomfort during the procedure.
Dilation and curettage (DC) — In a D&C, the cervix or opening of the uterus is dilated, and instruments are inserted and used to remove endometrial or uterine tissue. A D&C usually requires anesthesia. It may be used to more completely sample the tissue inside the uterus. It can sometimes be used as a treatment for prolonged or excessive bleeding that is due to hormonal changes and that is unresponsive to other treatments. (See "Patient information: Dilation and curettage (D&C)").
TREATMENT — The treatment of abnormal bleeding is based upon the underlying cause.
Oral contraceptives — Oral contraceptives are often used to treat uterine bleeding that is due to hormonal changes or hormonal irregularities. Oral contraceptives may be used in women who do not ovulate regularly to establish regular bleeding cycles and prevent excessive growth of the endometrium. In women who do ovulate, they may be used to treat excessive menstrual bleeding. Nonsteroidal anti-inflammatory drugs (NSAIDS, eg ibuprofen, naproxen sodium) may also be helpful in reducing blood loss and cramping in these women.
During perimenopause, oral contraceptives or other hormonal therapy may be used to regulate menstruation and prevent excessive growth of the endometrium. (See "Patient information: Menorrhagia (Excessive menstrual bleeding)").
Intrauterine device — An intrauterine contraceptive device (IUD) that secretes progestin may be recommended for women who do not ovulate regularly. IUDs are devices that are inserted by a healthcare provider into the uterus through the vagina and cervix. Most are made of molded plastic and include an attached plastic string that projects through the cervix, enabling the woman to check that the device remains in place (show picture 1).
Levonorgestrel-releasing IUDs decrease menstrual blood loss by 40 to 50 percent and decrease pain associated with periods. Some women completely stop having menstrual bleeding as a result of the IUD, although this effect is reversible if the IUD is removed. (See "Patient information: Contraception").
Surgery — Surgery may be necessary to remove abnormal uterine structures. Women who have completed childbearing who have heavy menstrual bleeding can consider a surgical procedure such as endometrial ablation. This procedure is done while the woman is under general or regional anesthesia, and uses heat, cold, or a laser to destroy the lining of the uterus.
Women with fibroids can have surgical treatment of their fibroids, either by removing the fibroid(s) (eg, myomectomy) or by reducing the blood supply of the fibroids (eg, uterine artery embolization). (See "Patient information: Fibroids").
Bleeding due to endometrial cancer, systemic diseases such as hypothyroidism or clotting disorders, or infection require treatment of the specific cause.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
American Academy of Family Physicians
(www.familydoctor.org)
The Nemours Foundation
(www.kidshealth.org, search for menstrual)
The Hormone Foundation
(www.hormone.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Bayer, SR, DeCherney, AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA 1993; 269:1823.
2. Awwad, JT, Toth, TL, Schiff, I. Abnormal uterine bleeding in the perimenopause. Int J Fertil Menopausal Stud 1993; 38:261.
3. Farquhar, CM, Lethaby, A, Sowter, M, et al. An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol 1999; 181:525.
4. Iatrakis, G, Diakakis, I, Kourounis, G, et al. Postmenopausal uterine bleeding. Clin Exp Obstet Gynecol 1997; 24:157.
Abnormal uterine bleeding can be caused by many different conditions. A history and physical examination are important first steps in determining the cause.
CAUSES — While most conditions that cause abnormal uterine bleeding can occur at any age, some are more likely to occur at particular times in a woman's life.
Bleeding before menarche — Bleeding before menarche (the first period in a girl's life) is always abnormal and can be caused by trauma, a foreign body (such as toys, coins, or toilet tissue), irritation of the genital area (due to bubble bath, soaps, lotions, or infection), or urinary tract problems. Bleeding can also occur as a result of sexual abuse.
Adolescents — Many girls have episodes of irregular bleeding during the first few years after their periods begin. This usually resolves without treatment when the girl's hormonal cycle and ovulation normalizes. If bleeding persists beyond this time, or if the bleeding is heavy, further evaluation is needed.
Abnormal bleeding in this age group can also be caused by pregnancy, bleeding disorders, some medical illnesses, and infection.
Birth control pills — Girls and women who use oral contraceptives may experience "breakthrough" bleeding between periods. If this occurs during the first months of oral contraceptive use, it may be due to changes in the lining of the uterus. If it persists for more than several months, a different oral contraceptive may be prescribed.
Breakthrough bleeding can also happen if the oral contraceptive is not taken regularly. If this occurs, the breakthrough bleeding may be an indication that the pill is not effective. Additional contraception may be necessary until the oral contraceptives are taken on a regular schedule and the breakthrough bleeding stops. If an adolescent has persistent breakthrough bleeding, further evaluation is needed.
Premenopausal women — Many different conditions can cause abnormal bleeding in women between adolescence and menopause. Abrupt changes in hormone levels at the time of expected ovulation can cause vaginal spotting, or small amounts of bleeding. As noted above, breakthrough bleeding can occur in women who use oral contraceptives.
In women who do not ovulate regularly (anovulatory women), irregular changes in hormone levels can cause bleeding to occur intermittently and in varying amounts. Although anovulation is most common when periods first begin and during perimenopause, it can occur at any time during the reproductive years. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Among women who ovulate normally, some experience excessive blood loss during their periods or bleed between periods. The most common causes of such bleeding are uterine fibroids or polyps. These irregular growths and benign tumors are composed of uterine tissue that distort the structure of the uterus and lead to abnormal uterine bleeding. Fibroids and polyps can also occur in anovulatory women. (See "Patient information: Fibroids" and see "Patient information: Menorrhagia (Excessive menstrual bleeding)").
Other causes of abnormal uterine bleeding in premenopausal women include: Pregnancy Cancer of the endometrium (lining of the uterus) or benign precancerous endometrial lesions Endometritis or inflammation of the endometrium A pelvic or vaginal infection Clotting disorders such as von Willebrand disease, platelet abnormalities, or problems with clotting factors Some systemic illnesses such as hypothyroidism, liver disease, or chronic renal disease
Perimenopausal women — Before menstruation stops, a woman passes through a period called perimenopause. During perimenopause, normal hormonal cycling begins to change and ovulation may be inconsistent. While estrogen secretion continues, progesterone secretion declines. These hormonal changes can cause the endometrium to grow and produce excess tissue, increasing the chances that polyps or endometrial hyperplasia (thickened lining of the uterus) will develop and potentially cause abnormal bleeding. Women in perimenopause are also at risk for other conditions that cause abnormal bleeding, including cancer, infection, and systemic illnesses. Further evaluation is indicated if a woman experiences persistent irregular menstrual cycles or an episode of profuse bleeding.
Women in perimenopause still ovulate some of the time and can become pregnant; pregnancy can cause abnormal bleeding. In addition, women in perimenopause may use hormonal contraceptive medications, which can cause breakthrough bleeding.
Menopausal women — A number of conditions can cause abnormal bleeding during the menopause. Many women are on hormone replacement therapy at some point during menopause and may experience cyclical bleeding. Any other bleeding that occurs during menopause is abnormal and should be investigated. Causes of abnormal bleeding during menopause include: Atrophy or thinning of the tissue lining the vagina and uterus Cancer of the uterine lining or endometrium Polyps or fibroids Endometrial hyperplasia Infection of the uterus Use of blood thinners or anticoagulants Side effects of radiation therapy
EVALUATION
Initial assessment — While taking a woman's medical history, a clinician will review a number of factors that can help identify the cause of abnormal bleeding. These include: the duration and quantity of the bleeding; factors that seem to bring the bleeding on; symptoms that occur along with the bleeding such as pain, fever, or vaginal odor; the relationship between bleeding and sexual relations; whether there is a personal or family history of bleeding disorders; the woman's medical history and medications she is taking; and whether the woman has experienced a weight change, stress, started a new exercise program, or has any underlying medical problems.
The clinician will perform a general physical exam to evaluate the woman's overall health, and a pelvic examination to confirm that the bleeding is from the uterus and not from another site like the external genitals or the rectum. During the pelvic exam, the clinician will look for any obvious lesions (cuts, sores, or tumors) and will examine the size and shape of the uterus. They will examine the cervix to look for signs of cervical bleeding, and a Pap smear may be obtained to examine the cells of the cervix (the lower end of the uterus, where it opens to the vagina).
In addition to a careful history and physical examination, laboratory tests and diagnostic procedures may be used to identify the cause of abnormal bleeding.
Lab tests — In premenopausal women, a pregnancy test is usually performed. If there is any abnormal vaginal discharge, a culture may be performed. Lab tests may also be conducted to determine whether there are problems with blood clotting or other systemic conditions, such as hypothyroidism, liver disease, or kidney problems.
Tests to determine ovulatory status — Because hormonal irregularities can contribute to abnormal uterine bleeding, blood tests may be performed in premenopausal women to determine whether they ovulate (produce an egg) during each monthly cycle. As an example, a woman may be asked to record when her periods begin and end for several months and to note any premenstrual changes, like cramps or breast tenderness, that occur. Progesterone, which is released at the time of ovulation, may be measured with a blood test.
Endometrial assessment — Tests that assess the endometrium (lining of the uterus) may be performed to rule out endometrial cancer and structural abnormalities such as uterine fibroids or polyps. Such tests include:
Endometrial biopsy — An endometrial biopsy is often performed in women over age 35 to rule out endometrial cancer or unusual endometrial growths. A biopsy may also be performed in women younger than 35 if they have risk factors for endometrial cancer. Risks include obesity, chronic anovulation, history of breast cancer, tamoxifen use or a family history of breast cancer or some other cancers. During the biopsy, a thin instrument is inserted through the vagina into the uterus to obtain a small sample of endometrial tissue. The biopsy can be performed in a healthcare provider's office without anesthesia. Because only a small portion of the endometrium is sampled, the biopsy may miss some causes of bleeding and other tests may be necessary.
Transvaginal ultrasound — An ultrasound uses sound waves to measure an organ's shape and structure. In a transvaginal ultrasound, a small ultrasound probe is inserted into the vagina so that it is closer to the uterus and can provide a cleare image of uterine contents. A transvaginal ultrasound is a minimally invasive way to determine whether abnormal uterine structures, or signs of excessive endometrial growth, are present. However, because it cannot distinguish between different types of structural abnormalities, further testing may be necessary if any are found.
Saline infusion sonography or sonohysterography — In this test, a transvaginal ultrasound is performed after sterile saline is instilled into the uterus. This procedure gives a better picture of the inside of the uterus, and small lesions can be more easily detected. However, because tissue samples cannot be obtained during the procedure, a final diagnosis is not always possible and additional evaluation through hysteroscopy or dilation and curettage (D&C) may be necessary.
Magnetic resonance imaging (MRI) — MRI is non-invasive and uses a magnetic field and radio waves to visualize organs. It is sometimes used to determine the presence of fibroids or other structural abnormalities.
Hysteroscopy — In a hysteroscopy, a small scope is inserted through the cervix and into the uterus. Air or fluid is injected to expand the uterus and to allow the physician to see the inside of the uterus. Tissue samples may be taken. Sedation with regional anesthesia (eg, spinal or epidural) or general anesthesia (medicine given to induce sleep) is used to minimize discomfort during the procedure.
Dilation and curettage (DC) — In a D&C, the cervix or opening of the uterus is dilated, and instruments are inserted and used to remove endometrial or uterine tissue. A D&C usually requires anesthesia. It may be used to more completely sample the tissue inside the uterus. It can sometimes be used as a treatment for prolonged or excessive bleeding that is due to hormonal changes and that is unresponsive to other treatments. (See "Patient information: Dilation and curettage (D&C)").
TREATMENT — The treatment of abnormal bleeding is based upon the underlying cause.
Oral contraceptives — Oral contraceptives are often used to treat uterine bleeding that is due to hormonal changes or hormonal irregularities. Oral contraceptives may be used in women who do not ovulate regularly to establish regular bleeding cycles and prevent excessive growth of the endometrium. In women who do ovulate, they may be used to treat excessive menstrual bleeding. Nonsteroidal anti-inflammatory drugs (NSAIDS, eg ibuprofen, naproxen sodium) may also be helpful in reducing blood loss and cramping in these women.
During perimenopause, oral contraceptives or other hormonal therapy may be used to regulate menstruation and prevent excessive growth of the endometrium. (See "Patient information: Menorrhagia (Excessive menstrual bleeding)").
Intrauterine device — An intrauterine contraceptive device (IUD) that secretes progestin may be recommended for women who do not ovulate regularly. IUDs are devices that are inserted by a healthcare provider into the uterus through the vagina and cervix. Most are made of molded plastic and include an attached plastic string that projects through the cervix, enabling the woman to check that the device remains in place (show picture 1).
Levonorgestrel-releasing IUDs decrease menstrual blood loss by 40 to 50 percent and decrease pain associated with periods. Some women completely stop having menstrual bleeding as a result of the IUD, although this effect is reversible if the IUD is removed. (See "Patient information: Contraception").
Surgery — Surgery may be necessary to remove abnormal uterine structures. Women who have completed childbearing who have heavy menstrual bleeding can consider a surgical procedure such as endometrial ablation. This procedure is done while the woman is under general or regional anesthesia, and uses heat, cold, or a laser to destroy the lining of the uterus.
Women with fibroids can have surgical treatment of their fibroids, either by removing the fibroid(s) (eg, myomectomy) or by reducing the blood supply of the fibroids (eg, uterine artery embolization). (See "Patient information: Fibroids").
Bleeding due to endometrial cancer, systemic diseases such as hypothyroidism or clotting disorders, or infection require treatment of the specific cause.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
American Academy of Family Physicians
(www.familydoctor.org)
The Nemours Foundation
(www.kidshealth.org, search for menstrual)
The Hormone Foundation
(www.hormone.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Bayer, SR, DeCherney, AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA 1993; 269:1823.
2. Awwad, JT, Toth, TL, Schiff, I. Abnormal uterine bleeding in the perimenopause. Int J Fertil Menopausal Stud 1993; 38:261.
3. Farquhar, CM, Lethaby, A, Sowter, M, et al. An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol 1999; 181:525.
4. Iatrakis, G, Diakakis, I, Kourounis, G, et al. Postmenopausal uterine bleeding. Clin Exp Obstet Gynecol 1997; 24:157.
Abnormal uterine bleeding
INTRODUCTION — Under normal circumstances, a woman's uterus sheds a limited amount of blood during each menstrual period. Bleeding that occurs between menstrual periods or excessive bleeding that occurs during menstruation is considered to be abnormal uterine bleeding. Once a woman enters menopause and menstrual cycles have ended, any bleeding, other than the small amounts that can occur in women on hormone replacement therapy, is considered abnormal.
Abnormal uterine bleeding can be caused by many different conditions. A history and physical examination are important first steps in determining the cause.
CAUSES — While most conditions that cause abnormal uterine bleeding can occur at any age, some are more likely to occur at particular times in a woman's life.
Bleeding before menarche — Bleeding before menarche (the first period in a girl's life) is always abnormal and can be caused by trauma, a foreign body (such as toys, coins, or toilet tissue), irritation of the genital area (due to bubble bath, soaps, lotions, or infection), or urinary tract problems. Bleeding can also occur as a result of sexual abuse.
Adolescents — Many girls have episodes of irregular bleeding during the first few years after their periods begin. This usually resolves without treatment when the girl's hormonal cycle and ovulation normalizes. If bleeding persists beyond this time, or if the bleeding is heavy, further evaluation is needed.
Abnormal bleeding in this age group can also be caused by pregnancy, bleeding disorders, some medical illnesses, and infection.
Birth control pills — Girls and women who use oral contraceptives may experience "breakthrough" bleeding between periods. If this occurs during the first months of oral contraceptive use, it may be due to changes in the lining of the uterus. If it persists for more than several months, a different oral contraceptive may be prescribed.
Breakthrough bleeding can also happen if the oral contraceptive is not taken regularly. If this occurs, the breakthrough bleeding may be an indication that the pill is not effective. Additional contraception may be necessary until the oral contraceptives are taken on a regular schedule and the breakthrough bleeding stops. If an adolescent has persistent breakthrough bleeding, further evaluation is needed.
Premenopausal women — Many different conditions can cause abnormal bleeding in women between adolescence and menopause. Abrupt changes in hormone levels at the time of expected ovulation can cause vaginal spotting, or small amounts of bleeding. As noted above, breakthrough bleeding can occur in women who use oral contraceptives.
In women who do not ovulate regularly (anovulatory women), irregular changes in hormone levels can cause bleeding to occur intermittently and in varying amounts. Although anovulation is most common when periods first begin and during perimenopause, it can occur at any time during the reproductive years. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Among women who ovulate normally, some experience excessive blood loss during their periods or bleed between periods. The most common causes of such bleeding are uterine fibroids or polyps. These irregular growths and benign tumors are composed of uterine tissue that distort the structure of the uterus and lead to abnormal uterine bleeding. Fibroids and polyps can also occur in anovulatory women. (See "Patient information: Fibroids" and see "Patient information: Menorrhagia (Excessive menstrual bleeding)").
Other causes of abnormal uterine bleeding in premenopausal women include: Pregnancy Cancer of the endometrium (lining of the uterus) or benign precancerous endometrial lesions Endometritis or inflammation of the endometrium A pelvic or vaginal infection Clotting disorders such as von Willebrand disease, platelet abnormalities, or problems with clotting factors Some systemic illnesses such as hypothyroidism, liver disease, or chronic renal disease
Perimenopausal women — Before menstruation stops, a woman passes through a period called perimenopause. During perimenopause, normal hormonal cycling begins to change and ovulation may be inconsistent. While estrogen secretion continues, progesterone secretion declines. These hormonal changes can cause the endometrium to grow and produce excess tissue, increasing the chances that polyps or endometrial hyperplasia (thickened lining of the uterus) will develop and potentially cause abnormal bleeding. Women in perimenopause are also at risk for other conditions that cause abnormal bleeding, including cancer, infection, and systemic illnesses. Further evaluation is indicated if a woman experiences persistent irregular menstrual cycles or an episode of profuse bleeding.
Women in perimenopause still ovulate some of the time and can become pregnant; pregnancy can cause abnormal bleeding. In addition, women in perimenopause may use hormonal contraceptive medications, which can cause breakthrough bleeding.
Menopausal women — A number of conditions can cause abnormal bleeding during the menopause. Many women are on hormone replacement therapy at some point during menopause and may experience cyclical bleeding. Any other bleeding that occurs during menopause is abnormal and should be investigated. Causes of abnormal bleeding during menopause include: Atrophy or thinning of the tissue lining the vagina and uterus Cancer of the uterine lining or endometrium Polyps or fibroids Endometrial hyperplasia Infection of the uterus Use of blood thinners or anticoagulants Side effects of radiation therapy
EVALUATION
Initial assessment — While taking a woman's medical history, a clinician will review a number of factors that can help identify the cause of abnormal bleeding. These include: the duration and quantity of the bleeding; factors that seem to bring the bleeding on; symptoms that occur along with the bleeding such as pain, fever, or vaginal odor; the relationship between bleeding and sexual relations; whether there is a personal or family history of bleeding disorders; the woman's medical history and medications she is taking; and whether the woman has experienced a weight change, stress, started a new exercise program, or has any underlying medical problems.
The clinician will perform a general physical exam to evaluate the woman's overall health, and a pelvic examination to confirm that the bleeding is from the uterus and not from another site like the external genitals or the rectum. During the pelvic exam, the clinician will look for any obvious lesions (cuts, sores, or tumors) and will examine the size and shape of the uterus. They will examine the cervix to look for signs of cervical bleeding, and a Pap smear may be obtained to examine the cells of the cervix (the lower end of the uterus, where it opens to the vagina).
In addition to a careful history and physical examination, laboratory tests and diagnostic procedures may be used to identify the cause of abnormal bleeding.
Lab tests — In premenopausal women, a pregnancy test is usually performed. If there is any abnormal vaginal discharge, a culture may be performed. Lab tests may also be conducted to determine whether there are problems with blood clotting or other systemic conditions, such as hypothyroidism, liver disease, or kidney problems.
Tests to determine ovulatory status — Because hormonal irregularities can contribute to abnormal uterine bleeding, blood tests may be performed in premenopausal women to determine whether they ovulate (produce an egg) during each monthly cycle. As an example, a woman may be asked to record when her periods begin and end for several months and to note any premenstrual changes, like cramps or breast tenderness, that occur. Progesterone, which is released at the time of ovulation, may be measured with a blood test.
Endometrial assessment — Tests that assess the endometrium (lining of the uterus) may be performed to rule out endometrial cancer and structural abnormalities such as uterine fibroids or polyps. Such tests include:
Endometrial biopsy — An endometrial biopsy is often performed in women over age 35 to rule out endometrial cancer or unusual endometrial growths. A biopsy may also be performed in women younger than 35 if they have risk factors for endometrial cancer. Risks include obesity, chronic anovulation, history of breast cancer, tamoxifen use or a family history of breast cancer or some other cancers. During the biopsy, a thin instrument is inserted through the vagina into the uterus to obtain a small sample of endometrial tissue. The biopsy can be performed in a healthcare provider's office without anesthesia. Because only a small portion of the endometrium is sampled, the biopsy may miss some causes of bleeding and other tests may be necessary.
Transvaginal ultrasound — An ultrasound uses sound waves to measure an organ's shape and structure. In a transvaginal ultrasound, a small ultrasound probe is inserted into the vagina so that it is closer to the uterus and can provide a cleare image of uterine contents. A transvaginal ultrasound is a minimally invasive way to determine whether abnormal uterine structures, or signs of excessive endometrial growth, are present. However, because it cannot distinguish between different types of structural abnormalities, further testing may be necessary if any are found.
Saline infusion sonography or sonohysterography — In this test, a transvaginal ultrasound is performed after sterile saline is instilled into the uterus. This procedure gives a better picture of the inside of the uterus, and small lesions can be more easily detected. However, because tissue samples cannot be obtained during the procedure, a final diagnosis is not always possible and additional evaluation through hysteroscopy or dilation and curettage (D&C) may be necessary.
Magnetic resonance imaging (MRI) — MRI is non-invasive and uses a magnetic field and radio waves to visualize organs. It is sometimes used to determine the presence of fibroids or other structural abnormalities.
Hysteroscopy — In a hysteroscopy, a small scope is inserted through the cervix and into the uterus. Air or fluid is injected to expand the uterus and to allow the physician to see the inside of the uterus. Tissue samples may be taken. Sedation with regional anesthesia (eg, spinal or epidural) or general anesthesia (medicine given to induce sleep) is used to minimize discomfort during the procedure.
Dilation and curettage (DC) — In a D&C, the cervix or opening of the uterus is dilated, and instruments are inserted and used to remove endometrial or uterine tissue. A D&C usually requires anesthesia. It may be used to more completely sample the tissue inside the uterus. It can sometimes be used as a treatment for prolonged or excessive bleeding that is due to hormonal changes and that is unresponsive to other treatments. (See "Patient information: Dilation and curettage (D&C)").
TREATMENT — The treatment of abnormal bleeding is based upon the underlying cause.
Oral contraceptives — Oral contraceptives are often used to treat uterine bleeding that is due to hormonal changes or hormonal irregularities. Oral contraceptives may be used in women who do not ovulate regularly to establish regular bleeding cycles and prevent excessive growth of the endometrium. In women who do ovulate, they may be used to treat excessive menstrual bleeding. Nonsteroidal anti-inflammatory drugs (NSAIDS, eg ibuprofen, naproxen sodium) may also be helpful in reducing blood loss and cramping in these women.
During perimenopause, oral contraceptives or other hormonal therapy may be used to regulate menstruation and prevent excessive growth of the endometrium. (See "Patient information: Menorrhagia (Excessive menstrual bleeding)").
Intrauterine device — An intrauterine contraceptive device (IUD) that secretes progestin may be recommended for women who do not ovulate regularly. IUDs are devices that are inserted by a healthcare provider into the uterus through the vagina and cervix. Most are made of molded plastic and include an attached plastic string that projects through the cervix, enabling the woman to check that the device remains in place (show picture 1).
Levonorgestrel-releasing IUDs decrease menstrual blood loss by 40 to 50 percent and decrease pain associated with periods. Some women completely stop having menstrual bleeding as a result of the IUD, although this effect is reversible if the IUD is removed. (See "Patient information: Contraception").
Surgery — Surgery may be necessary to remove abnormal uterine structures. Women who have completed childbearing who have heavy menstrual bleeding can consider a surgical procedure such as endometrial ablation. This procedure is done while the woman is under general or regional anesthesia, and uses heat, cold, or a laser to destroy the lining of the uterus.
Women with fibroids can have surgical treatment of their fibroids, either by removing the fibroid(s) (eg, myomectomy) or by reducing the blood supply of the fibroids (eg, uterine artery embolization). (See "Patient information: Fibroids").
Bleeding due to endometrial cancer, systemic diseases such as hypothyroidism or clotting disorders, or infection require treatment of the specific cause.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
American Academy of Family Physicians
(www.familydoctor.org)
The Nemours Foundation
(www.kidshealth.org, search for menstrual)
The Hormone Foundation
(www.hormone.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Bayer, SR, DeCherney, AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA 1993; 269:1823.
2. Awwad, JT, Toth, TL, Schiff, I. Abnormal uterine bleeding in the perimenopause. Int J Fertil Menopausal Stud 1993; 38:261.
3. Farquhar, CM, Lethaby, A, Sowter, M, et al. An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol 1999; 181:525.
4. Iatrakis, G, Diakakis, I, Kourounis, G, et al. Postmenopausal uterine bleeding. Clin Exp Obstet Gynecol 1997; 24:157.
Abnormal uterine bleeding can be caused by many different conditions. A history and physical examination are important first steps in determining the cause.
CAUSES — While most conditions that cause abnormal uterine bleeding can occur at any age, some are more likely to occur at particular times in a woman's life.
Bleeding before menarche — Bleeding before menarche (the first period in a girl's life) is always abnormal and can be caused by trauma, a foreign body (such as toys, coins, or toilet tissue), irritation of the genital area (due to bubble bath, soaps, lotions, or infection), or urinary tract problems. Bleeding can also occur as a result of sexual abuse.
Adolescents — Many girls have episodes of irregular bleeding during the first few years after their periods begin. This usually resolves without treatment when the girl's hormonal cycle and ovulation normalizes. If bleeding persists beyond this time, or if the bleeding is heavy, further evaluation is needed.
Abnormal bleeding in this age group can also be caused by pregnancy, bleeding disorders, some medical illnesses, and infection.
Birth control pills — Girls and women who use oral contraceptives may experience "breakthrough" bleeding between periods. If this occurs during the first months of oral contraceptive use, it may be due to changes in the lining of the uterus. If it persists for more than several months, a different oral contraceptive may be prescribed.
Breakthrough bleeding can also happen if the oral contraceptive is not taken regularly. If this occurs, the breakthrough bleeding may be an indication that the pill is not effective. Additional contraception may be necessary until the oral contraceptives are taken on a regular schedule and the breakthrough bleeding stops. If an adolescent has persistent breakthrough bleeding, further evaluation is needed.
Premenopausal women — Many different conditions can cause abnormal bleeding in women between adolescence and menopause. Abrupt changes in hormone levels at the time of expected ovulation can cause vaginal spotting, or small amounts of bleeding. As noted above, breakthrough bleeding can occur in women who use oral contraceptives.
In women who do not ovulate regularly (anovulatory women), irregular changes in hormone levels can cause bleeding to occur intermittently and in varying amounts. Although anovulation is most common when periods first begin and during perimenopause, it can occur at any time during the reproductive years. (See "Patient information: Menstrual cycle disorders (Absent and irregular periods)").
Among women who ovulate normally, some experience excessive blood loss during their periods or bleed between periods. The most common causes of such bleeding are uterine fibroids or polyps. These irregular growths and benign tumors are composed of uterine tissue that distort the structure of the uterus and lead to abnormal uterine bleeding. Fibroids and polyps can also occur in anovulatory women. (See "Patient information: Fibroids" and see "Patient information: Menorrhagia (Excessive menstrual bleeding)").
Other causes of abnormal uterine bleeding in premenopausal women include: Pregnancy Cancer of the endometrium (lining of the uterus) or benign precancerous endometrial lesions Endometritis or inflammation of the endometrium A pelvic or vaginal infection Clotting disorders such as von Willebrand disease, platelet abnormalities, or problems with clotting factors Some systemic illnesses such as hypothyroidism, liver disease, or chronic renal disease
Perimenopausal women — Before menstruation stops, a woman passes through a period called perimenopause. During perimenopause, normal hormonal cycling begins to change and ovulation may be inconsistent. While estrogen secretion continues, progesterone secretion declines. These hormonal changes can cause the endometrium to grow and produce excess tissue, increasing the chances that polyps or endometrial hyperplasia (thickened lining of the uterus) will develop and potentially cause abnormal bleeding. Women in perimenopause are also at risk for other conditions that cause abnormal bleeding, including cancer, infection, and systemic illnesses. Further evaluation is indicated if a woman experiences persistent irregular menstrual cycles or an episode of profuse bleeding.
Women in perimenopause still ovulate some of the time and can become pregnant; pregnancy can cause abnormal bleeding. In addition, women in perimenopause may use hormonal contraceptive medications, which can cause breakthrough bleeding.
Menopausal women — A number of conditions can cause abnormal bleeding during the menopause. Many women are on hormone replacement therapy at some point during menopause and may experience cyclical bleeding. Any other bleeding that occurs during menopause is abnormal and should be investigated. Causes of abnormal bleeding during menopause include: Atrophy or thinning of the tissue lining the vagina and uterus Cancer of the uterine lining or endometrium Polyps or fibroids Endometrial hyperplasia Infection of the uterus Use of blood thinners or anticoagulants Side effects of radiation therapy
EVALUATION
Initial assessment — While taking a woman's medical history, a clinician will review a number of factors that can help identify the cause of abnormal bleeding. These include: the duration and quantity of the bleeding; factors that seem to bring the bleeding on; symptoms that occur along with the bleeding such as pain, fever, or vaginal odor; the relationship between bleeding and sexual relations; whether there is a personal or family history of bleeding disorders; the woman's medical history and medications she is taking; and whether the woman has experienced a weight change, stress, started a new exercise program, or has any underlying medical problems.
The clinician will perform a general physical exam to evaluate the woman's overall health, and a pelvic examination to confirm that the bleeding is from the uterus and not from another site like the external genitals or the rectum. During the pelvic exam, the clinician will look for any obvious lesions (cuts, sores, or tumors) and will examine the size and shape of the uterus. They will examine the cervix to look for signs of cervical bleeding, and a Pap smear may be obtained to examine the cells of the cervix (the lower end of the uterus, where it opens to the vagina).
In addition to a careful history and physical examination, laboratory tests and diagnostic procedures may be used to identify the cause of abnormal bleeding.
Lab tests — In premenopausal women, a pregnancy test is usually performed. If there is any abnormal vaginal discharge, a culture may be performed. Lab tests may also be conducted to determine whether there are problems with blood clotting or other systemic conditions, such as hypothyroidism, liver disease, or kidney problems.
Tests to determine ovulatory status — Because hormonal irregularities can contribute to abnormal uterine bleeding, blood tests may be performed in premenopausal women to determine whether they ovulate (produce an egg) during each monthly cycle. As an example, a woman may be asked to record when her periods begin and end for several months and to note any premenstrual changes, like cramps or breast tenderness, that occur. Progesterone, which is released at the time of ovulation, may be measured with a blood test.
Endometrial assessment — Tests that assess the endometrium (lining of the uterus) may be performed to rule out endometrial cancer and structural abnormalities such as uterine fibroids or polyps. Such tests include:
Endometrial biopsy — An endometrial biopsy is often performed in women over age 35 to rule out endometrial cancer or unusual endometrial growths. A biopsy may also be performed in women younger than 35 if they have risk factors for endometrial cancer. Risks include obesity, chronic anovulation, history of breast cancer, tamoxifen use or a family history of breast cancer or some other cancers. During the biopsy, a thin instrument is inserted through the vagina into the uterus to obtain a small sample of endometrial tissue. The biopsy can be performed in a healthcare provider's office without anesthesia. Because only a small portion of the endometrium is sampled, the biopsy may miss some causes of bleeding and other tests may be necessary.
Transvaginal ultrasound — An ultrasound uses sound waves to measure an organ's shape and structure. In a transvaginal ultrasound, a small ultrasound probe is inserted into the vagina so that it is closer to the uterus and can provide a cleare image of uterine contents. A transvaginal ultrasound is a minimally invasive way to determine whether abnormal uterine structures, or signs of excessive endometrial growth, are present. However, because it cannot distinguish between different types of structural abnormalities, further testing may be necessary if any are found.
Saline infusion sonography or sonohysterography — In this test, a transvaginal ultrasound is performed after sterile saline is instilled into the uterus. This procedure gives a better picture of the inside of the uterus, and small lesions can be more easily detected. However, because tissue samples cannot be obtained during the procedure, a final diagnosis is not always possible and additional evaluation through hysteroscopy or dilation and curettage (D&C) may be necessary.
Magnetic resonance imaging (MRI) — MRI is non-invasive and uses a magnetic field and radio waves to visualize organs. It is sometimes used to determine the presence of fibroids or other structural abnormalities.
Hysteroscopy — In a hysteroscopy, a small scope is inserted through the cervix and into the uterus. Air or fluid is injected to expand the uterus and to allow the physician to see the inside of the uterus. Tissue samples may be taken. Sedation with regional anesthesia (eg, spinal or epidural) or general anesthesia (medicine given to induce sleep) is used to minimize discomfort during the procedure.
Dilation and curettage (DC) — In a D&C, the cervix or opening of the uterus is dilated, and instruments are inserted and used to remove endometrial or uterine tissue. A D&C usually requires anesthesia. It may be used to more completely sample the tissue inside the uterus. It can sometimes be used as a treatment for prolonged or excessive bleeding that is due to hormonal changes and that is unresponsive to other treatments. (See "Patient information: Dilation and curettage (D&C)").
TREATMENT — The treatment of abnormal bleeding is based upon the underlying cause.
Oral contraceptives — Oral contraceptives are often used to treat uterine bleeding that is due to hormonal changes or hormonal irregularities. Oral contraceptives may be used in women who do not ovulate regularly to establish regular bleeding cycles and prevent excessive growth of the endometrium. In women who do ovulate, they may be used to treat excessive menstrual bleeding. Nonsteroidal anti-inflammatory drugs (NSAIDS, eg ibuprofen, naproxen sodium) may also be helpful in reducing blood loss and cramping in these women.
During perimenopause, oral contraceptives or other hormonal therapy may be used to regulate menstruation and prevent excessive growth of the endometrium. (See "Patient information: Menorrhagia (Excessive menstrual bleeding)").
Intrauterine device — An intrauterine contraceptive device (IUD) that secretes progestin may be recommended for women who do not ovulate regularly. IUDs are devices that are inserted by a healthcare provider into the uterus through the vagina and cervix. Most are made of molded plastic and include an attached plastic string that projects through the cervix, enabling the woman to check that the device remains in place (show picture 1).
Levonorgestrel-releasing IUDs decrease menstrual blood loss by 40 to 50 percent and decrease pain associated with periods. Some women completely stop having menstrual bleeding as a result of the IUD, although this effect is reversible if the IUD is removed. (See "Patient information: Contraception").
Surgery — Surgery may be necessary to remove abnormal uterine structures. Women who have completed childbearing who have heavy menstrual bleeding can consider a surgical procedure such as endometrial ablation. This procedure is done while the woman is under general or regional anesthesia, and uses heat, cold, or a laser to destroy the lining of the uterus.
Women with fibroids can have surgical treatment of their fibroids, either by removing the fibroid(s) (eg, myomectomy) or by reducing the blood supply of the fibroids (eg, uterine artery embolization). (See "Patient information: Fibroids").
Bleeding due to endometrial cancer, systemic diseases such as hypothyroidism or clotting disorders, or infection require treatment of the specific cause.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
American Academy of Family Physicians
(www.familydoctor.org)
The Nemours Foundation
(www.kidshealth.org, search for menstrual)
The Hormone Foundation
(www.hormone.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Bayer, SR, DeCherney, AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA 1993; 269:1823.
2. Awwad, JT, Toth, TL, Schiff, I. Abnormal uterine bleeding in the perimenopause. Int J Fertil Menopausal Stud 1993; 38:261.
3. Farquhar, CM, Lethaby, A, Sowter, M, et al. An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol 1999; 181:525.
4. Iatrakis, G, Diakakis, I, Kourounis, G, et al. Postmenopausal uterine bleeding. Clin Exp Obstet Gynecol 1997; 24:157.
Postmenopausal hormone therapy
DEFINING MENOPAUSE — With the onset of menopause, a woman's body stops making estrogen and progesterone. Estrogen and progesterone are the female hormones produced by the ovaries that prepare the uterus for possible pregnancy. Prior to menopause, (which usually occurs between the ages of 45 and 55), many women notice that their periods start to occur more frequently (as often as every 21 days), although periods eventually become infrequent. This time of "transition," called perimenopause, can last for several years until menopause, when periods stop altogether.
The average age of menopause is between 50 and 51 years, although some women experience unusually early menopause (before age 40) due to surgical removal of the uterus or both ovaries, chemotherapy, or radiation therapy. However, most cases of early menopause are unexplained.
Hot flashes — Hot flashes (or hot flushes) occur because of a fall in estrogen levels. Hot flashes often begin several years before menopause and continue for several years after menopause. They are far more common at night, and can disrupt sleep. Therefore, many women also experience symptoms related to sleep-deprivation, such as fatigue, irritability, difficulty concentrating, and mood swings.
Vaginal and urinary symptoms — Many women begin to experience vaginal dryness or urinary symptoms, both of which are related to estrogen deficiency. Estrogen is the most effective treatment available for hot flashes, vaginal dryness, and urinary symptoms.
Estrogen has important effects on many other organs, such as the brain, skin, blood vessels, heart, bone, and breast. Of particular importance are the effects of estrogen on bone and possibly cardiovascular (heart) health. Without estrogen, the body is at greater risk of developing osteoporosis, a disease in which bones lose calcium and become more susceptible to fracture. In addition, the risk of heart disease in women increases after menopause, although taking estrogen (hormone replacement therapy) has not been shown to prevent heart disease.
HORMONE REPLACEMENT THERAPY — Estrogen replacement therapy, also called ERT, is a way for a postmenopausal woman to replace the estrogen her body is no longer making. While it does not make her fertile again, it does eliminate many of the symptoms of menopause. Women with a uterus who take estrogen must also take a progesterone-like hormone (called progestins) to eliminate the risk of uterine (endometrial) cancer. The term hormone replacement therapy (HRT) is used when estrogen and progestin are given together.
HISTORY OF HRT USE — Estrogen first became popular in the 1960's for the treatment of hot flushes. At that time, it was also thought that estrogen helped to preserve a woman's youthful appearance. Early on, high doses of estrogen were given (as an example, 2.5 mg of conjugated estrogens compared to the standard 0.625 mg dose that is currently used). Since then, the regimens and the reasons for taking it have changed. Taking estrogen alone results in an increased risk of endometrial cancer (also known as uterine cancer). Adding a progestin to estrogen can prevent the increased endometrial cancer risk. Therefore, by the mid-1980s, progestins were routinely added to estrogen replacement therapy (in any woman with an intact uterus, ie, women who had not undergone a hysterectomy). Many studies showed that taking ERT or HRT could prevent the bone loss that occurs after menopause, which can lead to osteoporosis and its fractures. Over 30 studies suggested that estrogen was an important therapy for preventing or reducing the risk of coronary heart disease (CHD). In fact, it appeared that women taking estrogen reduced their risk of a first heart attack by 50 percent. In addition, estrogen appeared to reduce recurrent events in women who already had coronary disease. Because of the osteoporosis and CHD studies, ERT and HRT began to be prescribed for the prevention of both diseases, which meant giving it long-term (more than five years). Breast cancer studies began to indicate that taking ERT more than 5 years increased the risk of breast cancer. Clinical trials, (studies in which women are randomly assigned to receive active treatment or placebo), did not agree with the earlier studies. The Women's Health Initiative (WHI) and the HERS trials (of combined estrogen-progestin therapy) demonstrated that HRT did not prevent heart disease, and in fact, might increase risk. The WHI trial of combined estrogen-progestin therapy did show an increased risk of breast cancer, but there was no increased risk of breast cancer in women who took estrogen alone [1].
One possible explanation for the conflicting results between the observational studies and clinical trials, is that the observational studies had a problem with "healthy user bias". This means that the healthiest women (ie. those who were less apt to have a heart attack), were more likely to be started on estrogen by their physicians. Therefore, it is possible that estrogen's beneficial effect on the heart was more related to the underlying health of the women taking it, rather than the medication itself.
WOMEN'S HEALTH INITIATIVE — The Women's Health Initiative (WHI) is a set of clinical trials that includes two HRT trials. The WHI studied healthy postmenopausal women aged 50 to 79 years, and the study was scheduled to be completed in 2005. However, one component of the WHI (continuous, combined conjugated estrogen (CEE 0.625 mg/day) and medroxyprogesterone acetate (MPA 2.5 mg/day) versus placebo in over 16,000 women) was discontinued in 2002 because of an increased risk of coronary heart disease, breast cancer, stroke, and venous thromboembolism (blood clots in the leg or lung) over an average follow-up of 5.2 years [2]. Although there was reduction in risk of osteoporotic fractures and colon cancer, there was concern that the risks of combined estrogen-progestin may outweigh the benefits.
The WHI trial of unopposed estrogen (CEE 0.625 mg/day) versus placebo in women who had undergone hysterectomy (and therefore did not require a progestin) was also discontinued (early 2004) because of a small increase in stroke risk (but no increase in CHD or breast cancer risk) [1].
Only one type of estrogen (CEE 0.625 mg) and one type of progestin (MPA 2.5 mg) treatment were studied in the WHI brand names Premarin (unopposed estrogen) and Prempro (estrogen combined with progestin). Although there are theoretical reasons to believe that other types of estrogen and progestin, different routes of administration (skin patch) or lower doses might be safer, to date, there are no studies to demonstrate that this is true.
The results of the WHI were as follows [2]:
Coronary heart disease — The rate of coronary events such as heart attacks was 24 percent higher in the women taking HRT compared to those taking placebo. This seems like a large increase in risk, but the increase for an individual woman is low. As an example, on average there were 39 CHD events per year per 10,000 women versus 33 events per 10,000 women taking placebo (ie, an additional 6 events per 10,000 women per year).
The difference in coronary events developed within the first year of the study. The risk persisted in years two through five of the study, but the highest risk was in the first year. Taking a daily aspirin did not seem to reduce the risk.
In contrast, the WHI trial of unopposed estrogen did not observe an increase in CHD risk. In the younger women in the trial (ages 50-59), a possible protective effect was seen with estrogen (although this was not significant).
The WHI investigators subsequently reported that women ages 50 to 59 years at baseline, who had been menopausal for less than 10 years, did not have an increased risk of heart disease. The excess risk was only seen in older women in the trial. This was true for both the combined estrogen-progestin trial and the unopposed estrogen trial.
Prevention of CHD after a heart attack was evaluated in the HERS trials with 2763 postmenopausal women [3]. After nearly 7 years of follow-up, continuous estrogen-progestin therapy did not reduce the risk of CHD events in women with established CHD.
Stroke — The rate of stroke was increased with combined estrogen-progestin. On average per year, there were 29 strokes in the treatment group versus 21 events in the placebo group per 10,000 women (8 additional cases per 10,000 women per year). Most of the increase in risk was due to nonfatal strokes, and the increase did not appear until year two of the study (but persisted through year five). A very similar pattern of risk was seen in the trial of unopposed estrogen [1]. (See "Patient information: Stroke").
Blood clots — The rate of blood clots (in the leg and lung) increased with combined estrogen-progestin (34 versus 16 per 10,000 women per year; or 18 additional cases per 10,000 women per year). Risk was also increased with unopposed estrogen. (See "Patient information: Venous thrombosis").
Breast cancer — The risk of breast cancer was increased in the WHI trial of combined estrogen-progestin. On average, per year there were 38 cases of breast cancer per 10,000 women versus 30 per 10,000 women (8 additional cases per year per 10,000 women). Similar findings have been noted in a number of observational studies, all of which suggest that the major increase in risk occurs after taking estrogen-progestin for four or five years. In addition, the WHI reported that women taking combined estrogen-progestin were more likely to have an abnormal mammogram. However, the majority of the abnormal mammograms were requests to return for additional views.
The results of the trial of unopposed estrogen were quite surprising, because no increase of breast cancer was seen. In fact, a possible lower risk was seen, but this was not quite significant. The fact that an increase in breast cancer risk was seen with combined hormone therapy, but not with unopposed estrogen, suggests that the progestin component is a very important factor in the risk of developing breast cancer. (See "Patient information: Postmenopausal hormone therapy and breast cancer").
Osteoporotic fracture — The risk of osteoporotic fracture was reduced at the hip and spine in both the trial of combined estrogen-progestin and the trial of unopposed estrogen. On average, per year there were 5 fewer hip fractures per 10,000 women in the HRT versus placebo group. (See "Patient information: Osteoporosis prevention and treatment").
Colorectal cancer — The risk of colorectal cancer was reduced (6 fewer colorectal cancers per 10,000 women per year) in the trial of combined estrogen-progestin versus placebo group. This benefit was not seen in the trial of unopposed estrogen. (See "Patient information: Screening for colon cancer").
Cognitive function and dementia — Although it was thought that estrogen could preserve cognitive function and prevent dementia, data from the WHI do not support this. No significant improvement in overall cognitive function was seen with combined estrogen-progestin therapy compared with placebo. It is still possible, however, that there are benefits for certain specific types of cognitive function, although this is not proven. The impact of unopposed estrogen, or taking HRT in the early postmenopausal years is not known.
In addition, combined estrogen-progestin therapy did not prevent dementia. To the contrary, an increased risk was seen (approximately 23 additional cases of dementia per 10,000 women per year). It is not known why dementia risk was higher with hormone therapy, but one possible explanation is an increased risk of multiple small strokes (which predisposes women to dementia). Similar results were reported in the unopposed estrogen trial. The effect of taking HRT in the early menopausal years on the risk of later dementia is not known, although many early studies suggest that it is early, rather than late, exposure to estrogen is important for later cognitive function.
Endometrial hyperplasia and cancer — Studies have found that postmenopausal women with a uterus who are treated with estrogen alone increase their risk of endometrial cancer and hyperplasia (a precursor to cancer). Within one year, endometrial hyperplasia can be found in 20 to 50 percent of women receiving estrogen alone. The risk can be even greater if very high doses are used or if the unopposed estrogen is continued for many years. Even when women discontinue the estrogen, the endometrial cancer risk persists for approximately five years.
In the WHI, only women without a uterus received unopposed estrogen. In women with a uterus who received combined estrogen-progestin therapy, there was no increased risk of endometrial hyperplasia or cancer.
Absolute risk of an adverse event — It should be emphasized that the absolute risk of an adverse event occurring in an individual on the estrogen-progestin regimen in the WHI was extremely low (19 additional events per year per 10,000 women with HRT compared to placebo).
In the trial of unopposed estrogen, it was calculated that overall risks and benefits would be equal (not taking into account the effect that estrogen has on hot flashes).
Most now agree that using either unopposed estrogen or combined estrogen-progestin therapy for symptom relief in young postmenopausal women in a safe and reasonable option.
OTHER RISKS — There are many HRT studies in addition to the WHI that provide other information about breast cancer. In addition, there are other known risks of HRT such as gallbladder disease that were not addressed in the WHI report.
Other breast cancer issues — The degree of increase in breast cancer risk due to estrogen is often misinterpreted. It is most important for a woman to understand the absolute risk that she will get breast cancer because she takes estrogen. It has been calculated that for a 50-year-old woman taking estrogen, there is a 1 in 100 chance that she will develop breast cancer over a 10-year period that would not have developed without estrogen. This estimate would be slightly higher (eg, 1.5 in 100) for a woman over 65 years of age.
Many studies have reported that if breast cancer does occur during estrogen therapy, it is biologically less aggressive, and survival rates are better than when breast cancer occurs in women who were not taking estrogen. However, in the WHI combined estrogen-progestin trial, women on hormones had tumors that were slightly larger and more likely to have spread to the lymph nodes. As mentioned above, no increase in breast cancer risk was seen in the trial of unopposed estrogen.
Gallbladder disease — There is considerable evidence that estrogen therapy, especially in pill form, is associated with an increased risk of gallbladder disease. The risk of cholecystectomy, (removal of the gallbladder), increases the longer a woman uses hormone therapy and the higher the dose of estrogen used. The risk decreases substantially within one to three years after a woman discontinues hormone therapy.
OTHER BENEFITS — In addition to easing the symptoms of menopause, ER/HRT has many other positive effects.
Menopausal symptoms — Estrogen is the most effective treatment available for symptoms such as hot flashes, urinary symptoms, and vaginal atrophy (atrophic vaginitis), a condition in which the vagina can become dry, resulting in pain with intercourse.
Quality of life — Women with severe menopausal symptoms often describe a dramatic improvement in their quality of life when they are treated with estrogen. This is due to relief of hot flushes and restoration of normal sleep.
Urinary tract infection — Estrogen has been found to decrease the frequency of urinary tract infections, possibly by normalizing the microorganisms present in the vagina. It does not help the symptoms of urinary incontinence. (See "Patient information: Urinary tract infection in adults").
Diabetes mellitus — The WHI reported that HRT appears to reduce the risk of type 2 diabetes mellitus (adult onset diabetes). However, because of the other risks of HRT, this effect is insufficient to recommend HRT for routine diabetes prevention in postmenopausal women. (See "Patient information: Diabetes mellitus, type 2").
Depression — Estrogen may improve mood and decrease depression in some menopausal women. One study showed that estrogen plus progestin was effective in perimenopausal women with depression. (See "Patient information: Depression in adults").
WHO SHOULD TAKE HRT?— Data from the WHI and the HERS trials have led to changes in our recommendations for hormone therapy [2,3]. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. Unopposed estrogen increases the risk of stroke, but overall, its benefits seem equal to its risks. As a result, the main reason to take hormone therapy at present is to control menopausal symptoms.
Menopausal symptoms — Estrogen or combined estrogen-progestin therapy remains the gold standard for relief of menopausal symptoms, and therefore is a reasonable option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous blood clot or stroke, or those at high risk for these complications. In otherwise healthy women, the absolute risk of an adverse event is extremely low. Most experts agree that hormone therapy is safe and reasonable for healthy postmenopausal women who need to take it to relieve symptoms. When it is used, is should be taken for the shortest period of time possible.
Administration of estrogen short-term is not associated with an increased risk of breast cancer, but endometrial hyperplasia and cancer can occur after as little as six months of unopposed estrogen therapy; as a result, a progestin must be added in those women who have not had a hysterectomy.
In women being treated for symptoms, the goal is to eventually taper and stop the estrogen (unless there is a compelling reason to continue it long-term). After the planned treatment interval, the estrogen should be discontinued gradually, as an example, by omitting one pill per week, to minimize recurrence of the menopausal symptoms.
Low-dose oral contraceptives — A low-estrogen oral contraceptive (20 µg of ethinyl estradiol) remains an appropriate treatment for perimenopausal women who seek relief of menopausal symptoms. Most of these women are between the ages of 40 and 50 years and are still candidates for oral contraception. For them, an oral contraceptive pill containing 20 µg of ethinyl estradiol provides symptomatic relief, contraception, and sometimes better bleeding control than conventional estrogen-progestin therapy. (See "Patient information: Hormonal methods of birth control").
Dose of estrogen — It is possible that lower doses of estrogen may be safer than estrogen, while still effectively treating menopausal symptoms. As an example, conjugated estrogens (0.3 mg) or the equivalent dose of other estrogens (estradiol, estrogen patch) have been shown in some, but not all studies to relieve symptoms and prevent bone loss. But it is not yet known whether lower doses of estrogen or different HRT preparations are safer with regards to breast cancer and cardiovascular risks. Therefore, it is safest to assume that other preparations carry the same risk.
Long-term estrogen therapy — Only a minority of women who are unable to successfully discontinue estrogen without persistent symptoms should consider long-term estrogen therapy. If HRT is resumed, the lowest dose possible should be used, and plans should be made to try another taper at a later date. It is important that the breast cancer and cardiovascular risks are discussed in detail with these women.
TYPES OF ESTROGEN — Estrogen can be taken as a pill (orally), or absorbed through the skin from a patch (transdermally), or inserted into the vagina.
Estrogen pill — There are many forms of estrogen pills. The most commonly used preparation, called Premarin, is made from pregnant mares' urine. Many other preparations are derived from plant sources, such as soy and yams. While there is no evidence that plant-derived estrogens work better or are safer than Premarin, many women prefer them.
Sometimes the dose of estrogen is large enough to protect bones, but not to completely eliminate menopausal symptoms. When these symptoms occur, a larger dose may be given for a year or two, but then the dose is usually reduced.
Besides Premarin, other brands of estrogen include: Cenestin, Estratab, Menest, Ogen, Estrace, and Gynediol. While these preparations vary in their potency and dose amounts, they are all effective.
Estrogen patch — There are many brands of estrogen patches. Those available in the United States include: Estraderm, Climara, Vivelle, FemPatch, and Alora. Some patches need to be replaced every few days, others once a week.
If an equivalent dose is given, transdermal estrogen is just as effective as oral estrogens in increasing bone density and in treating menopausal symptoms. But unlike oral estrogen, it has not been shown to have a beneficial effect on cholesterol levels.
Vaginal estrogen — Vaginal estrogen is available as a cream, vaginal ring, or vaginal tablet. Estrogen cream is inserted into the vagina using an applicator once a day for two to three weeks. After this, the frequency may be reduced to one or two times weekly. The estrogen vaginal tablet (Vagifem®) is given on a similar schedule.
The vaginal ring, called Estring, is a flexible plastic ring. It is inserted once every three months and does not need to be removed during intercourse or bathing. Estring may be preferred by women who have trouble using vaginal cream on a regular basis, or in women with reproductive organs that may be sagging, called prolapse, who would benefit from additional support.
Vaginal estrogen is an excellent choice for women who want to control vaginal dryness or prevent frequent urinary tract infections. Unlike the estrogen in pills and patches, very little vaginal estrogen is absorbed by the rest of the body. As a result, vaginal estrogen does not have the other positive or negative effects.
There is one vaginal estrogen product for postmenopausal women that contains a higher dose of estrogen (Femring®). This ring contains a higher dose of estrogen that is absorbed into the bloodstream to relieve hot flashes. We do not recommend Femring for women who need vaginal estrogen to relieve vaginal dryness or urinary symptoms.
TYPES OF PROGESTIN — As noted above, progestins are now routinely added to estrogen for any woman with a uterus. The most commonly prescribed progestin is medroxyprogesterone acetate, available in pill form under the brand names Provera, Cycrin, or Amen. There are other progestin preparations, like those used in oral contraceptives, but none have obvious advantages over medroxyprogesterone. A natural progesterone, called Prometrium®, may be a good alternative for women who cannot tolerate medroxyprogesterone. In addition, natural progesterone has no negative effect on lipids, and therefore is a good choice in women with underlying high cholesterol levels.
ALTERNATIVES TO ERT/HRT — Not all women are able or willing to take estrogen replacement, and alternative therapies are available. These are discussed in detail elsewhere (See "Patient information: Alternatives to postmenopausal hormone therapy").
BREAST CANCER AND ESTROGEN — Although women with breast cancer often experience early menopause due to adjuvant chemotherapy, and may have vasomotor symptoms due to tamoxifen therapy, estrogen therapy (by mouth or patch) is generally not recommended.
In a study called the HABITS trial, 434 women with breast cancer were randomly assigned to receive two years of HRT (estrogen alone or with progestin depending upon hysterectomy status) or no hormones [4]. After 2 years of follow-up, women in the estrogen groups were at least three times more likely to have a recurrence than women who did not take hormones. Based upon the excessive risk in the hormone group, the study was terminated in December 2003.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Hormone Foundation
(www.hormone.org/public/menopause.cfm, available in English and Spanish)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Anderson, GL, Limacher, M, Assaf, AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701.
2. Rossouw, JE, Anderson, GL, Prentice, RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321.
3. Grady, D, Herrington, D, Bittner, V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49.
4. Holmberg, L, Anderson, H. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363:453.
The average age of menopause is between 50 and 51 years, although some women experience unusually early menopause (before age 40) due to surgical removal of the uterus or both ovaries, chemotherapy, or radiation therapy. However, most cases of early menopause are unexplained.
Hot flashes — Hot flashes (or hot flushes) occur because of a fall in estrogen levels. Hot flashes often begin several years before menopause and continue for several years after menopause. They are far more common at night, and can disrupt sleep. Therefore, many women also experience symptoms related to sleep-deprivation, such as fatigue, irritability, difficulty concentrating, and mood swings.
Vaginal and urinary symptoms — Many women begin to experience vaginal dryness or urinary symptoms, both of which are related to estrogen deficiency. Estrogen is the most effective treatment available for hot flashes, vaginal dryness, and urinary symptoms.
Estrogen has important effects on many other organs, such as the brain, skin, blood vessels, heart, bone, and breast. Of particular importance are the effects of estrogen on bone and possibly cardiovascular (heart) health. Without estrogen, the body is at greater risk of developing osteoporosis, a disease in which bones lose calcium and become more susceptible to fracture. In addition, the risk of heart disease in women increases after menopause, although taking estrogen (hormone replacement therapy) has not been shown to prevent heart disease.
HORMONE REPLACEMENT THERAPY — Estrogen replacement therapy, also called ERT, is a way for a postmenopausal woman to replace the estrogen her body is no longer making. While it does not make her fertile again, it does eliminate many of the symptoms of menopause. Women with a uterus who take estrogen must also take a progesterone-like hormone (called progestins) to eliminate the risk of uterine (endometrial) cancer. The term hormone replacement therapy (HRT) is used when estrogen and progestin are given together.
HISTORY OF HRT USE — Estrogen first became popular in the 1960's for the treatment of hot flushes. At that time, it was also thought that estrogen helped to preserve a woman's youthful appearance. Early on, high doses of estrogen were given (as an example, 2.5 mg of conjugated estrogens compared to the standard 0.625 mg dose that is currently used). Since then, the regimens and the reasons for taking it have changed. Taking estrogen alone results in an increased risk of endometrial cancer (also known as uterine cancer). Adding a progestin to estrogen can prevent the increased endometrial cancer risk. Therefore, by the mid-1980s, progestins were routinely added to estrogen replacement therapy (in any woman with an intact uterus, ie, women who had not undergone a hysterectomy). Many studies showed that taking ERT or HRT could prevent the bone loss that occurs after menopause, which can lead to osteoporosis and its fractures. Over 30 studies suggested that estrogen was an important therapy for preventing or reducing the risk of coronary heart disease (CHD). In fact, it appeared that women taking estrogen reduced their risk of a first heart attack by 50 percent. In addition, estrogen appeared to reduce recurrent events in women who already had coronary disease. Because of the osteoporosis and CHD studies, ERT and HRT began to be prescribed for the prevention of both diseases, which meant giving it long-term (more than five years). Breast cancer studies began to indicate that taking ERT more than 5 years increased the risk of breast cancer. Clinical trials, (studies in which women are randomly assigned to receive active treatment or placebo), did not agree with the earlier studies. The Women's Health Initiative (WHI) and the HERS trials (of combined estrogen-progestin therapy) demonstrated that HRT did not prevent heart disease, and in fact, might increase risk. The WHI trial of combined estrogen-progestin therapy did show an increased risk of breast cancer, but there was no increased risk of breast cancer in women who took estrogen alone [1].
One possible explanation for the conflicting results between the observational studies and clinical trials, is that the observational studies had a problem with "healthy user bias". This means that the healthiest women (ie. those who were less apt to have a heart attack), were more likely to be started on estrogen by their physicians. Therefore, it is possible that estrogen's beneficial effect on the heart was more related to the underlying health of the women taking it, rather than the medication itself.
WOMEN'S HEALTH INITIATIVE — The Women's Health Initiative (WHI) is a set of clinical trials that includes two HRT trials. The WHI studied healthy postmenopausal women aged 50 to 79 years, and the study was scheduled to be completed in 2005. However, one component of the WHI (continuous, combined conjugated estrogen (CEE 0.625 mg/day) and medroxyprogesterone acetate (MPA 2.5 mg/day) versus placebo in over 16,000 women) was discontinued in 2002 because of an increased risk of coronary heart disease, breast cancer, stroke, and venous thromboembolism (blood clots in the leg or lung) over an average follow-up of 5.2 years [2]. Although there was reduction in risk of osteoporotic fractures and colon cancer, there was concern that the risks of combined estrogen-progestin may outweigh the benefits.
The WHI trial of unopposed estrogen (CEE 0.625 mg/day) versus placebo in women who had undergone hysterectomy (and therefore did not require a progestin) was also discontinued (early 2004) because of a small increase in stroke risk (but no increase in CHD or breast cancer risk) [1].
Only one type of estrogen (CEE 0.625 mg) and one type of progestin (MPA 2.5 mg) treatment were studied in the WHI brand names Premarin (unopposed estrogen) and Prempro (estrogen combined with progestin). Although there are theoretical reasons to believe that other types of estrogen and progestin, different routes of administration (skin patch) or lower doses might be safer, to date, there are no studies to demonstrate that this is true.
The results of the WHI were as follows [2]:
Coronary heart disease — The rate of coronary events such as heart attacks was 24 percent higher in the women taking HRT compared to those taking placebo. This seems like a large increase in risk, but the increase for an individual woman is low. As an example, on average there were 39 CHD events per year per 10,000 women versus 33 events per 10,000 women taking placebo (ie, an additional 6 events per 10,000 women per year).
The difference in coronary events developed within the first year of the study. The risk persisted in years two through five of the study, but the highest risk was in the first year. Taking a daily aspirin did not seem to reduce the risk.
In contrast, the WHI trial of unopposed estrogen did not observe an increase in CHD risk. In the younger women in the trial (ages 50-59), a possible protective effect was seen with estrogen (although this was not significant).
The WHI investigators subsequently reported that women ages 50 to 59 years at baseline, who had been menopausal for less than 10 years, did not have an increased risk of heart disease. The excess risk was only seen in older women in the trial. This was true for both the combined estrogen-progestin trial and the unopposed estrogen trial.
Prevention of CHD after a heart attack was evaluated in the HERS trials with 2763 postmenopausal women [3]. After nearly 7 years of follow-up, continuous estrogen-progestin therapy did not reduce the risk of CHD events in women with established CHD.
Stroke — The rate of stroke was increased with combined estrogen-progestin. On average per year, there were 29 strokes in the treatment group versus 21 events in the placebo group per 10,000 women (8 additional cases per 10,000 women per year). Most of the increase in risk was due to nonfatal strokes, and the increase did not appear until year two of the study (but persisted through year five). A very similar pattern of risk was seen in the trial of unopposed estrogen [1]. (See "Patient information: Stroke").
Blood clots — The rate of blood clots (in the leg and lung) increased with combined estrogen-progestin (34 versus 16 per 10,000 women per year; or 18 additional cases per 10,000 women per year). Risk was also increased with unopposed estrogen. (See "Patient information: Venous thrombosis").
Breast cancer — The risk of breast cancer was increased in the WHI trial of combined estrogen-progestin. On average, per year there were 38 cases of breast cancer per 10,000 women versus 30 per 10,000 women (8 additional cases per year per 10,000 women). Similar findings have been noted in a number of observational studies, all of which suggest that the major increase in risk occurs after taking estrogen-progestin for four or five years. In addition, the WHI reported that women taking combined estrogen-progestin were more likely to have an abnormal mammogram. However, the majority of the abnormal mammograms were requests to return for additional views.
The results of the trial of unopposed estrogen were quite surprising, because no increase of breast cancer was seen. In fact, a possible lower risk was seen, but this was not quite significant. The fact that an increase in breast cancer risk was seen with combined hormone therapy, but not with unopposed estrogen, suggests that the progestin component is a very important factor in the risk of developing breast cancer. (See "Patient information: Postmenopausal hormone therapy and breast cancer").
Osteoporotic fracture — The risk of osteoporotic fracture was reduced at the hip and spine in both the trial of combined estrogen-progestin and the trial of unopposed estrogen. On average, per year there were 5 fewer hip fractures per 10,000 women in the HRT versus placebo group. (See "Patient information: Osteoporosis prevention and treatment").
Colorectal cancer — The risk of colorectal cancer was reduced (6 fewer colorectal cancers per 10,000 women per year) in the trial of combined estrogen-progestin versus placebo group. This benefit was not seen in the trial of unopposed estrogen. (See "Patient information: Screening for colon cancer").
Cognitive function and dementia — Although it was thought that estrogen could preserve cognitive function and prevent dementia, data from the WHI do not support this. No significant improvement in overall cognitive function was seen with combined estrogen-progestin therapy compared with placebo. It is still possible, however, that there are benefits for certain specific types of cognitive function, although this is not proven. The impact of unopposed estrogen, or taking HRT in the early postmenopausal years is not known.
In addition, combined estrogen-progestin therapy did not prevent dementia. To the contrary, an increased risk was seen (approximately 23 additional cases of dementia per 10,000 women per year). It is not known why dementia risk was higher with hormone therapy, but one possible explanation is an increased risk of multiple small strokes (which predisposes women to dementia). Similar results were reported in the unopposed estrogen trial. The effect of taking HRT in the early menopausal years on the risk of later dementia is not known, although many early studies suggest that it is early, rather than late, exposure to estrogen is important for later cognitive function.
Endometrial hyperplasia and cancer — Studies have found that postmenopausal women with a uterus who are treated with estrogen alone increase their risk of endometrial cancer and hyperplasia (a precursor to cancer). Within one year, endometrial hyperplasia can be found in 20 to 50 percent of women receiving estrogen alone. The risk can be even greater if very high doses are used or if the unopposed estrogen is continued for many years. Even when women discontinue the estrogen, the endometrial cancer risk persists for approximately five years.
In the WHI, only women without a uterus received unopposed estrogen. In women with a uterus who received combined estrogen-progestin therapy, there was no increased risk of endometrial hyperplasia or cancer.
Absolute risk of an adverse event — It should be emphasized that the absolute risk of an adverse event occurring in an individual on the estrogen-progestin regimen in the WHI was extremely low (19 additional events per year per 10,000 women with HRT compared to placebo).
In the trial of unopposed estrogen, it was calculated that overall risks and benefits would be equal (not taking into account the effect that estrogen has on hot flashes).
Most now agree that using either unopposed estrogen or combined estrogen-progestin therapy for symptom relief in young postmenopausal women in a safe and reasonable option.
OTHER RISKS — There are many HRT studies in addition to the WHI that provide other information about breast cancer. In addition, there are other known risks of HRT such as gallbladder disease that were not addressed in the WHI report.
Other breast cancer issues — The degree of increase in breast cancer risk due to estrogen is often misinterpreted. It is most important for a woman to understand the absolute risk that she will get breast cancer because she takes estrogen. It has been calculated that for a 50-year-old woman taking estrogen, there is a 1 in 100 chance that she will develop breast cancer over a 10-year period that would not have developed without estrogen. This estimate would be slightly higher (eg, 1.5 in 100) for a woman over 65 years of age.
Many studies have reported that if breast cancer does occur during estrogen therapy, it is biologically less aggressive, and survival rates are better than when breast cancer occurs in women who were not taking estrogen. However, in the WHI combined estrogen-progestin trial, women on hormones had tumors that were slightly larger and more likely to have spread to the lymph nodes. As mentioned above, no increase in breast cancer risk was seen in the trial of unopposed estrogen.
Gallbladder disease — There is considerable evidence that estrogen therapy, especially in pill form, is associated with an increased risk of gallbladder disease. The risk of cholecystectomy, (removal of the gallbladder), increases the longer a woman uses hormone therapy and the higher the dose of estrogen used. The risk decreases substantially within one to three years after a woman discontinues hormone therapy.
OTHER BENEFITS — In addition to easing the symptoms of menopause, ER/HRT has many other positive effects.
Menopausal symptoms — Estrogen is the most effective treatment available for symptoms such as hot flashes, urinary symptoms, and vaginal atrophy (atrophic vaginitis), a condition in which the vagina can become dry, resulting in pain with intercourse.
Quality of life — Women with severe menopausal symptoms often describe a dramatic improvement in their quality of life when they are treated with estrogen. This is due to relief of hot flushes and restoration of normal sleep.
Urinary tract infection — Estrogen has been found to decrease the frequency of urinary tract infections, possibly by normalizing the microorganisms present in the vagina. It does not help the symptoms of urinary incontinence. (See "Patient information: Urinary tract infection in adults").
Diabetes mellitus — The WHI reported that HRT appears to reduce the risk of type 2 diabetes mellitus (adult onset diabetes). However, because of the other risks of HRT, this effect is insufficient to recommend HRT for routine diabetes prevention in postmenopausal women. (See "Patient information: Diabetes mellitus, type 2").
Depression — Estrogen may improve mood and decrease depression in some menopausal women. One study showed that estrogen plus progestin was effective in perimenopausal women with depression. (See "Patient information: Depression in adults").
WHO SHOULD TAKE HRT?— Data from the WHI and the HERS trials have led to changes in our recommendations for hormone therapy [2,3]. Continuous estrogen-progestin therapy appears to increase the risk of cardiovascular events and breast cancer; in addition, other drugs (eg, bisphosphonates, raloxifene) can protect against osteoporosis. Unopposed estrogen increases the risk of stroke, but overall, its benefits seem equal to its risks. As a result, the main reason to take hormone therapy at present is to control menopausal symptoms.
Menopausal symptoms — Estrogen or combined estrogen-progestin therapy remains the gold standard for relief of menopausal symptoms, and therefore is a reasonable option for most postmenopausal women, with the exception of those with a history of breast cancer, CHD, a previous blood clot or stroke, or those at high risk for these complications. In otherwise healthy women, the absolute risk of an adverse event is extremely low. Most experts agree that hormone therapy is safe and reasonable for healthy postmenopausal women who need to take it to relieve symptoms. When it is used, is should be taken for the shortest period of time possible.
Administration of estrogen short-term is not associated with an increased risk of breast cancer, but endometrial hyperplasia and cancer can occur after as little as six months of unopposed estrogen therapy; as a result, a progestin must be added in those women who have not had a hysterectomy.
In women being treated for symptoms, the goal is to eventually taper and stop the estrogen (unless there is a compelling reason to continue it long-term). After the planned treatment interval, the estrogen should be discontinued gradually, as an example, by omitting one pill per week, to minimize recurrence of the menopausal symptoms.
Low-dose oral contraceptives — A low-estrogen oral contraceptive (20 µg of ethinyl estradiol) remains an appropriate treatment for perimenopausal women who seek relief of menopausal symptoms. Most of these women are between the ages of 40 and 50 years and are still candidates for oral contraception. For them, an oral contraceptive pill containing 20 µg of ethinyl estradiol provides symptomatic relief, contraception, and sometimes better bleeding control than conventional estrogen-progestin therapy. (See "Patient information: Hormonal methods of birth control").
Dose of estrogen — It is possible that lower doses of estrogen may be safer than estrogen, while still effectively treating menopausal symptoms. As an example, conjugated estrogens (0.3 mg) or the equivalent dose of other estrogens (estradiol, estrogen patch) have been shown in some, but not all studies to relieve symptoms and prevent bone loss. But it is not yet known whether lower doses of estrogen or different HRT preparations are safer with regards to breast cancer and cardiovascular risks. Therefore, it is safest to assume that other preparations carry the same risk.
Long-term estrogen therapy — Only a minority of women who are unable to successfully discontinue estrogen without persistent symptoms should consider long-term estrogen therapy. If HRT is resumed, the lowest dose possible should be used, and plans should be made to try another taper at a later date. It is important that the breast cancer and cardiovascular risks are discussed in detail with these women.
TYPES OF ESTROGEN — Estrogen can be taken as a pill (orally), or absorbed through the skin from a patch (transdermally), or inserted into the vagina.
Estrogen pill — There are many forms of estrogen pills. The most commonly used preparation, called Premarin, is made from pregnant mares' urine. Many other preparations are derived from plant sources, such as soy and yams. While there is no evidence that plant-derived estrogens work better or are safer than Premarin, many women prefer them.
Sometimes the dose of estrogen is large enough to protect bones, but not to completely eliminate menopausal symptoms. When these symptoms occur, a larger dose may be given for a year or two, but then the dose is usually reduced.
Besides Premarin, other brands of estrogen include: Cenestin, Estratab, Menest, Ogen, Estrace, and Gynediol. While these preparations vary in their potency and dose amounts, they are all effective.
Estrogen patch — There are many brands of estrogen patches. Those available in the United States include: Estraderm, Climara, Vivelle, FemPatch, and Alora. Some patches need to be replaced every few days, others once a week.
If an equivalent dose is given, transdermal estrogen is just as effective as oral estrogens in increasing bone density and in treating menopausal symptoms. But unlike oral estrogen, it has not been shown to have a beneficial effect on cholesterol levels.
Vaginal estrogen — Vaginal estrogen is available as a cream, vaginal ring, or vaginal tablet. Estrogen cream is inserted into the vagina using an applicator once a day for two to three weeks. After this, the frequency may be reduced to one or two times weekly. The estrogen vaginal tablet (Vagifem®) is given on a similar schedule.
The vaginal ring, called Estring, is a flexible plastic ring. It is inserted once every three months and does not need to be removed during intercourse or bathing. Estring may be preferred by women who have trouble using vaginal cream on a regular basis, or in women with reproductive organs that may be sagging, called prolapse, who would benefit from additional support.
Vaginal estrogen is an excellent choice for women who want to control vaginal dryness or prevent frequent urinary tract infections. Unlike the estrogen in pills and patches, very little vaginal estrogen is absorbed by the rest of the body. As a result, vaginal estrogen does not have the other positive or negative effects.
There is one vaginal estrogen product for postmenopausal women that contains a higher dose of estrogen (Femring®). This ring contains a higher dose of estrogen that is absorbed into the bloodstream to relieve hot flashes. We do not recommend Femring for women who need vaginal estrogen to relieve vaginal dryness or urinary symptoms.
TYPES OF PROGESTIN — As noted above, progestins are now routinely added to estrogen for any woman with a uterus. The most commonly prescribed progestin is medroxyprogesterone acetate, available in pill form under the brand names Provera, Cycrin, or Amen. There are other progestin preparations, like those used in oral contraceptives, but none have obvious advantages over medroxyprogesterone. A natural progesterone, called Prometrium®, may be a good alternative for women who cannot tolerate medroxyprogesterone. In addition, natural progesterone has no negative effect on lipids, and therefore is a good choice in women with underlying high cholesterol levels.
ALTERNATIVES TO ERT/HRT — Not all women are able or willing to take estrogen replacement, and alternative therapies are available. These are discussed in detail elsewhere (See "Patient information: Alternatives to postmenopausal hormone therapy").
BREAST CANCER AND ESTROGEN — Although women with breast cancer often experience early menopause due to adjuvant chemotherapy, and may have vasomotor symptoms due to tamoxifen therapy, estrogen therapy (by mouth or patch) is generally not recommended.
In a study called the HABITS trial, 434 women with breast cancer were randomly assigned to receive two years of HRT (estrogen alone or with progestin depending upon hysterectomy status) or no hormones [4]. After 2 years of follow-up, women in the estrogen groups were at least three times more likely to have a recurrence than women who did not take hormones. Based upon the excessive risk in the hormone group, the study was terminated in December 2003.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Hormone Foundation
(www.hormone.org/public/menopause.cfm, available in English and Spanish)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Anderson, GL, Limacher, M, Assaf, AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701.
2. Rossouw, JE, Anderson, GL, Prentice, RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321.
3. Grady, D, Herrington, D, Bittner, V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49.
4. Holmberg, L, Anderson, H. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363:453.
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