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1 Lakeview Endocrinology and Diabetes Consultants 2719 N Halsted St C-1 Chicago IL P: F: Patient information: Early menopause (premature ovarian failure) PREMATURE OVARIAN FAILURE OVERVIEW Premature ovarian failure (POF) is a condition in which the ovaries stop functioning normally in women who are younger than 40. The condition used to be called "premature menopause," but that term is misleading, because women with premature ovarian failure do not always stop menstruating, and their ovaries do not always completely shut down [1]. That's important to keep in mind, because the diagnosis of premature ovarian failure does not always mean that pregnancy is impossible. What's more, the condition does not imply that a woman is aging prematurely. It simply means that her ovaries are faltering. Another term used for POF is primary ovarian insufficiency (POI). This term is likely to replace the term POF in the near future. In women with premature ovarian failure, the ovaries: Stop releasing eggs, or release them only intermittently; and Stop producing the hormones estrogen and progesterone, or produce them only intermittently. Given these effects, premature ovarian failure makes pregnancy unlikely. Learning of this can be emotionally devastating to some women, especially if they have not had children or want more children. For them, the diagnosis squelches dreams of motherhood. If that is true for you, take some time to learn about your options. Take time, too, to honor your feelings of grief and loss. Being diagnosed with premature ovarian failure can be a life-changing experience [2]. It is natural to feel down, but be mindful of depression.

2 You may even want to seek out counseling or to participate in a support group for women with premature ovarian failure. If you have a partner, remember that he or she may also be affected by your diagnosis, so it might be useful to find support for the two of you. PREMATURE OVARIAN FAILURE CAUSES In the vast majority of cases, healthcare providers do not know why premature ovarian failure occurs. Some cases of the condition can be explained by genetic abnormalities, exposure to toxins, or autoimmune disorders, but most cases are "idiopathic," meaning they have no known cause [3]. Even so, it's important for women to be tested for the known causes of premature ovarian failure. Some of the known causes may be associated with other effects on your health or the health of your family members. Genetic causes Genetic causes of premature ovarian failure may be due to abnormal chromosomes or abnormal individual genes. Chromosomes are structures that house thousands of genes. Chromosomal abnormalities that lead to premature ovarian failure include: Turner syndrome The sex of a person is determined by their complement of X and Y chromosomes. Women normally have two X chromosomes, while men have one X chromosome and one Y chromosome. In Turner syndrome, women have only one X chromosome; the other one is missing. The lack of a second X chromosome (Turner syndrome) is the most common chromosomal defect in humans. It causes abnormalities throughout the reproductive system and can cause premature ovarian failure. Missing just a portion of one X chromosome (a critical portion) can also cause premature ovarian failure. Fragile X syndrome Fragile X syndrome is the most common cause of intellectual disability (mental retardation) worldwide. People who have fragile X have a defective gene on the X chromosome. Those who have the defective gene do not always have mental retardation, but the genetic abnormality can worsen with each successive generation; hence, a woman whose premature ovarian failure is caused by a change in the fragile X gene is at risk of having an intellectually disabled baby, if she is able to conceive and give birth. For this reason, women who are carriers for the abnormality in the fragile X gene are advised to undergo genetic counseling before trying to get pregnant.

3 Other chromosomal and genetic causes Several other chromosomal and genetic abnormalities can lead to premature ovarian failure. For example, some women have Y chromosome material, even though the Y chromosome should exist only in men. Although this condition is rare, women who have Y chromosome material need to have their ovaries removed because the abnormality can cause ovarian tumors. Other genetic abnormalities that can cause premature ovarian failure include those that impair normal hormonal function. Toxic causes The most common causes of toxin-induced ovarian failure are chemotherapy drugs and radiation therapy, both of which are used to treat cancer (see "Ovarian failure due to anticancer drugs and radiation"). Other toxic causes of ovarian failure may include certain viruses. Autoimmune causes The job of the immune system is to identify and destroy foreign or abnormal cells that can cause infection, cancer, or other problems. Unfortunately, the immune system sometimes misdirects its efforts and begins attacking the body's normal, healthy cells. In some cases of premature ovarian failure, the immune system mistakenly attacks hormone-producing (endocrine) organs, including not only the ovaries but also the adrenal glands, the thyroid glands, and other structures. Women whose ovarian failure is caused by an autoimmune disorder should have their adrenal and thyroid function evaluated. If the adrenal glands are affected, it can cause a very serious and potentially life-threatening condition called primary adrenal insufficiency (Addison's disease).

4 PREMATURE OVARIAN FAILURE SYMPTOMS Most women with premature ovarian failure undergo a normal puberty and have regular periods before developing ovarian failure. The most common symptom that prompts them to seek medical care is missed or infrequent periods. Some women first notice that their periods are infrequent or absent when they stop taking birth control pills, but that does not mean that the pills caused premature ovarian failure. While taking the pill may mask the condition, it cannot cause it. Other premature ovarian failure symptoms include hot flashes or vaginal dryness, because women eventually produce little or no estrogen. As the condition progresses, some women may also develop vaginal inflammation and thinning of the vaginal walls, which can make intercourse painful. Family planning Premature ovarian failure often interferes with a woman's ability to get pregnant. Even so, between 5 and 10 percent of women with the condition are able to conceive and give birth normally. Others become pregnant through in vitro fertilization using donor eggs. PREMATURE OVARIAN FAILURE DIAGNOSIS If you are younger than 40 and have not had a regular period for three months or longer, see a healthcare provider for a full evaluation. Even if you do not want to get pregnant, the condition can have broad-reaching implications for your overall health. Women with premature ovarian failure are at increased risk for osteoporosis and possibly even heart disease, so it's important that the condition be detected early and managed appropriately. To determine the cause of your irregular, absent, or unusually light periods, your healthcare provider should ask whether: You have symptoms besides light, irregular, or absent periods. Some women with premature ovarian failure have hot flashes or vaginal dryness, and these symptoms hold clues about how the ovaries are working. You have had surgery on your ovaries, or received chemotherapy, or radiation therapy, as these all damage ovarian tissue.

5 You or any of your family members have any autoimmune diseases, such as polyglandular failure, hypothyroidism, Addison disease, vitiligo, myasthenia gravis, Graves' disease, Sjögren syndrome, lupus, hypoparathyroidism, recurrent mucocutaneous candidiasis, celiac disease, type 1 diabetes, or rheumatoid arthritis. A personal or family history of these conditions can point to autoimmune ovarian failure You have any symptoms of adrenal insufficiency, such as decreased appetite, weight loss, vague abdominal pain, weakness, fatigue, salt craving, or darkening of the skin. These symptoms are important, because roughly 3 percent of women with premature ovarian failure develop adrenal insufficiency. Any of your family members have premature ovarian failure. Approximately 10 percent of cases of ovarian failure run in families. You have a family history of fragile X syndrome, mental retardation, or developmental delay. A family history of these conditions suggests that fragile X syndrome could be involved in your diagnosis. You have any hearing loss, because some genetic causes of premature ovarian failure can cause deafness. Important tests In addition to asking you detailed questions about your personal and family history, and performing a physical examination, your healthcare provider should order a blood test to measure various hormone levels. To be diagnosed with premature ovarian failure, you must have elevated levels of a hormone called follicle stimulating hormone (FSH). High levels of FSH indicate that your brain is trying to stimulate the ovaries but the ovaries are not responding. That's important because the ovaries sometimes fail not because they are dysfunctional, but because the brain or the body's master gland, the pituitary, has stopped properly regulating ovarian function.

6 If blood tests confirm that you have premature ovarian failure, your healthcare provider should then look for a potential cause. Tests used to determine the cause of the disorder include: Karyotyping, which determines whether any chromosomal abnormalities exist; Antibody measurements, which can point to autoimmune causes of ovarian failure; and Various types of genetic testing. PREMATURE OVARIAN FAILURE TREATMENT Estrogen replacement One of the main goals of premature ovarian failure treatment is replacing the estrogen that the ovaries have stopped producing. That's important, because estrogen is vital to certain normal processes. The bones, for example, need estrogen stimulation to stay strong and resistant to fracture. Without estrogen, women with premature ovarian failure are at risk of developing the bone-thinning disease osteoporosis. There is also some controversial evidence that a lack of estrogen, particularly before the age of 50, can increase the risk of heart disease. What's more, without estrogen, women often develop symptoms of menopause, namely hot flashes, night sweats, sleep disturbance, and vaginal dryness. Estrogen therapy aims to prevent or alleviate all of these consequences of estrogen deficiency. However most women cannot take estrogen alone; they must combine it with a progestin (a form of progesterone) to prevent a condition that could lead to cancer of the uterus. Most experts currently recommend that women with premature ovarian failure should take estrogen until age 50 years, the average age of menopause. Type of estrogen therapy The main form of estrogen that the ovaries normally produce is called estradiol. Some experts believe that giving women this type of estrogen best mimics the "natural condition," but other forms of estrogen are available and are also effective.

7 Women who opt for estradiol can get it in pill form or in a patch that is worn on the skin. According to some doctors, the estradiol patch may offer advantages over the pill form, including that: It delivers the same hormone that the ovaries make It does not have to go through the liver to get into the bloodstream It gets into the body in a slow, steady stream, rather than all at once It can be measured easily in the bloodstream Despite the advantages the patch may have, other forms of estrogen replacement are also effective, and women should choose the form that best suits them. Some women do not like wearing the patch; others develop skin irritation when they wear it. For them, hormones in pill form may be a better choice. Regardless of the form of estrogen they choose, most women must also take some form of progestin (a type of progesterone). With progestins, women also have choices. They come in patch or pill form and there are synthetic and "natural" versions. For women who wish to avoid pregnancy, some healthcare providers prescribe oral contraceptives, because the estrogen doses used in hormone replacement are not high enough to prevent pregnancy. However, some providers suggest barrier contraception instead of the pill, because occasional women with POF have become pregnant in spite of taking the pill. Women who do want to get pregnant, meanwhile, should opt for a hormone combination that changes cyclically, the way estrogen and progestin do naturally. Women with POF commonly experience unpredictable and intermittent ovarian function, and it is estimated that there is a about a 4 percent chance of ovulating each month. Duration of estrogen therapy Women taking estrogen and progestin may worry about the risks of hormone replacement therapy. After all, recent studies have linked the use of these hormones with an elevated risk of heart attack, stroke, and breast cancer, among other things. The fact is, those studies looked at the effects of estrogen and progestin in women who were in their sixties and seventies and who had undergone menopause naturally.

8 The results of those studies do not apply to younger women with premature ovarian failure. On the contrary, studies in women with the condition suggest that they are more likely to have cardiovascular problems if they don't take hormones than if they do. Plus, forgoing hormones can lead to osteoporosis. Most experts agree, in general, that young women with premature ovarian failure should use hormone therapy at least until they turn 50. Infertility treatment As noted above, between 5 and 10 percent of women with POF are able to conceive and give birth normally without any special treatment. Treatment with estrogen, fertility drugs, or other hormones, has not been shown to improve fertility. One treatment that is successful is in vitro fertilization with donor eggs. In one report of 61 women with premature ovarian failure undergoing 90 treatment cycles, the cumulative chance of pregnancy after three cycles was approximately 90 percent. Success rates for this procedure depend primarily on the age of the egg donor. Embryo donation, in which frozen embryos are donated to the couple, is also often successful, and in general, less expensive. If you are interested in becoming pregnant, work with your healthcare provider to identify the cause of your condition before you start trying to conceive. Some underlying causes of premature ovarian failure can adversely affect a pregnancy or a fetus, if a pregnancy is successful. For some women, adoption is a good option. SUMMARY Being diagnosed with premature ovarian failure (also called primary ovarian insufficiency) can be emotionally trying. Women with the disorder may need time to grieve and adjust to the diagnosis, and there are resources that can help them do that. Women with premature ovarian failure should consider taking estrogen-progestin therapy at least until age 50 to prevent osteoporosis and possibly cardiovascular disease. Taking these hormones will have the added benefit of reducing menopausal symptoms, including hot flashes, night sweats, and vaginal dryness. Women interested in becoming pregnant should consult their own healthcare provider about possible therapeutic options. Those who are comfortable with pursuing assisted reproduction may want to consider in vitro fertilization using donor eggs or donor embryos.

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