Patient education: Primary ovarian insufficiency (Beyond the Basics)

OVERVIEW AND DEFINITIONS — Primary ovarian insufficiency (also called premature ovarian insufficiency) is a condition in which the ovaries spontaneously stop functioning normally in people who are younger than 40 years. People sometimes also use the term "premature ovarian failure."

The average age of natural menopause is age 50 to 51, but menopause anytime between the ages of 45 and 55 is considered normal. Menopause is when a person stops having monthly periods and the ovaries stop releasing eggs and stop making the hormones estrogen and progesterone. Doctors use the term "early menopause" when menopause occurs between age 40 and 45. The term "surgical menopause" is used when the ovaries are removed (eg, to prevent or treat cancer) before the person has gone through natural menopause.

When the ovaries stop working properly before age 40, doctors refer to it as primary ovarian insufficiency (POI). In most cases, is not clear why this happens. In people with POI, both of the following occur:

●The ovaries stop releasing eggs ("ovulation") or release them only intermittently.

●The ovaries stop producing the hormones estrogen and progesterone or produce them only intermittently.

Because the ovaries are not working consistently, a person with POI is unlikely to be able to get pregnant naturally. However, some people continue to have intermittent periods for some time, during which it may be possible to get pregnant. Sometimes people use the term "premature menopause" to describe POI, but this is not entirely accurate since the ovaries may continue to work intermittently for some time.

Being diagnosed with POI can be emotionally devastating, especially for people who were planning or hoping to become pregnant in the future. If that is true for you, it's important to take care of your emotional health, get support from others, and learn about your options. (See 'Family planning' below.)

CAUSES — Health care providers often do not know why primary ovarian insufficiency (POI) occurs. Many cases of the condition will likely be explained by genetic changes, exposure to certain "toxins" (eg, some drugs or chemicals), or autoimmune disorders. However, some cases are "idiopathic," meaning they have no known cause. Even so, it is important to be tested for the known causes of POI. 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 POI may be due to abnormal chromosomes or changes in individual genes. Chromosomes are structures that house thousands of genes. Chromosomal abnormalities that lead to POI include:

●Turner syndrome – The biologic sex of a person is determined by their X and Y chromosomes. Females normally have two X chromosomes, while males have one X chromosome and one Y chromosome. Females with Turner syndrome have only one X chromosome; the other one is missing. This is the most common chromosomal defect in humans. It causes abnormalities throughout the reproductive system and can cause POI. Missing a specific portion of one X chromosome can also cause POI.

●Fragile X syndrome – Fragile X syndrome is the most common cause of intellectual disability worldwide. People with fragile X have an abnormal gene on the X chromosome. Those who have the abnormal gene do not always have intellectual disability, but the genetic abnormality can worsen with each successive generation. In other words, if a person with POI caused by a change in the fragile X gene gets pregnant, they are at risk of having a baby with intellectual disability. For this reason, females who are "carriers" for the abnormality in the fragile X gene are advised to have genetic counseling before trying to get pregnant.

●Other chromosomal and genetic causes – A number of other chromosomal and genetic abnormalities can lead to POI. For example, some females have Y chromosome material, even though the Y chromosome typically exists only in males. Although this condition is rare, females who have Y chromosome material need to have their ovaries removed because the abnormality can cause ovarian tumors. Other genetic abnormalities that can cause POI include those that impair normal hormonal function.

Toxic causes — The most common causes of "toxin-induced" ovarian insufficiency are chemotherapy drugs and radiation therapy, both of which are used to treat cancer by killing cancer cells. Chemotherapy drugs are also often used to treat other diseases, such as severe rheumatoid arthritis.

Autoimmune causes — When it is working properly, the body's immune system identifies and destroys foreign or abnormal cells that can cause infection, cancer, or other problems. When a person has an "autoimmune" disorder, the immune system instead attacks the body's normal, healthy cells. In some cases of POI, 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.

People whose ovarian insufficiency is caused by an autoimmune disorder should have blood tests to evaluate their adrenal and thyroid. If the adrenal glands are affected, it can cause a very serious and potentially life-threatening condition called "primary adrenal insufficiency" (Addison's disease). (See "Patient education: Adrenal insufficiency (Beyond the Basics)".)

SYMPTOMS — Symptoms of primary ovarian insufficiency (POI) can include menstrual and hormonal changes, infertility, and emotional symptoms.

Menstrual changes — Most people with POI go through normal puberty and have regular periods before their ovaries stop working normally. They most often seek medical attention when their period becomes irregular or infrequent.

Some people first notice changes in their periods when they stop taking birth control pills. This does not mean that the pills caused POI, just that the hormones in the pills "masked" it.

Infertility — With POI, the ovaries eventually stop working, making it impossible to get pregnant naturally. Some people learn that they have POI when they get an evaluation after being unable to conceive for some time.

Despite the odds being low, between 5 and 10 percent of people with the condition are able to conceive and carry a pregnancy. This is because the ovaries sometimes work intermittently for some time before they stop working completely. Other people are able to become pregnant through in vitro fertilization (IVF) using donor eggs. (See 'Family planning' below.)

If you have POI and wish to avoid pregnancy, your health care provider will most likely recommend taking birth control pills. (See 'Birth control' below.)

Menopause symptoms — Because the body eventually produces little or no estrogen, people with POI can also have symptoms of menopause, like hot flashes, night sweats, and sleep disturbances. As the condition progresses, some people may also develop vaginal dryness and thinning of the vaginal walls, which can make sex painful. There are treatments that can help with these symptoms. (See "Patient education: Menopausal hormone therapy (Beyond the Basics)" and "Patient education: Non-estrogen treatments for menopausal symptoms (Beyond the Basics)".)

Emotional symptoms — It can be very upsetting to learn that you have POI, especially if you were planning to get pregnant in the future. It is normal to feel sad or stressed. Some people develop symptoms of depression or anxiety. If you are having trouble coping, talk to your health care provider; they can help you get support and treatment if you need it.

DIAGNOSIS — If you are younger than 40 years and have not had a regular period for three months or longer, see a health care provider for a full evaluation.

Even if you do not want to get pregnant, primary ovarian insufficiency (POI) can affect your overall health. People with POI who do not take hormone replacement (estrogen) are at increased risk for osteoporosis and 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 health care provider should ask whether:

●You have symptoms besides changes to your period – Some people with POI have hot flashes or vaginal dryness, and these symptoms hold clues about how the ovaries are working.

●You have had surgery on your ovaries, chemotherapy, or radiation therapy – These things all damage ovarian tissue.

●You or any of your family members have any autoimmune diseases – Examples include hypothyroidism, hyperthyroidism, or Addison's disease.

●You have any symptoms of adrenal insufficiency – These include 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 people with POI develop adrenal insufficiency.

●Any of your family members have POI – Approximately 10 percent of cases of ovarian insufficiency run in families.

●You have a family history of fragile X syndrome, intellectual disability, or developmental delay – A family history of these conditions suggests that fragile X syndrome could be involved in your diagnosis.

Important tests — In addition to asking you detailed questions about your personal and family history and doing a physical exam, your health care provider should order a blood test to measure various hormone levels.

To be diagnosed with POI, you must be under age 40, have irregular periods, and 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.

If blood tests confirm that you have POI, your health care provider should then look for a potential cause. Tests used to determine the cause of the disorder might include:

●Karyotyping, which determines whether any chromosomal abnormalities exist. (See 'Genetic causes' above.)

●Testing for antibodies against the adrenal gland, which determines if you have a specific type of ovarian autoimmunity. (See 'Autoimmune causes' above.)

●Testing for the gene mutation that causes fragile X syndrome. (See 'Genetic causes' above.)

MANAGEMENT

Self-care — Being diagnosed with primary ovarian insufficiency (POI) can affect both your physical and emotional well-being. Management of the condition must address both. There are multiple choices available to you if you want to grow your family. (See 'Family planning' below.)

Take time to honor your feelings of grief and loss. Being diagnosed with POI can be a life-changing experience. It is natural to feel down, but be mindful of symptoms that could indicate depression. It may help to seek out counseling, participate in a professionally monitored support group, or connect with other people living with POI. If you have a partner, it may help to involve them in counseling and getting support, too.

Estrogen replacement — One of the main goals of POI 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, people with POI are at risk of developing osteoporosis (a disease in which the bones are weaker than normal).

There is also evidence that a lack of estrogen before the age of 45 years can increase the risk of heart disease. This can also cause symptoms of menopause, including hot flashes, night sweats, sleep disturbance, and vaginal dryness (see 'Menopause symptoms' above). Estrogen therapy aims to prevent or relieve all of these consequences of estrogen deficiency. Most people cannot take estrogen alone; they must combine it with a progestin (a form of progesterone) to prevent a condition that could lead to overgrowth of the uterine lining and possible cancer of the uterus. People who do not have a uterus (ie, have had a hysterectomy) can take estrogen alone.

Type of estrogen therapy — The main form of estrogen that the ovaries normally produce is called estradiol. Some experts believe that this type of estrogen best mimics the "natural condition." Other types of effective estrogens are also available, such as "conjugated" estrogens, but most experts prefer estradiol.

Estradiol comes in many forms: a pill, a patch that is worn on the skin, gels or sprays applied to the skin, or a ring that is inserted into the vagina. All forms are equally effective. You and your health care provider can discuss your options and preferences. Some people prefer the convenience and lower cost of oral estradiol. However, if you have risk factors for blood clots or strokes (high blood pressure or a family history of blood clots or strokes at a young age), your provider will recommend the estradiol patch, gel, spray, or a vaginal ring rather than a pill.

Regardless of the form of estrogen you choose, you will likely also need to take some form of a progestin. Progestins are hormones that act like natural progesterone but may have a different structure. Most experts recommend natural progesterone (given orally) because it is identical to the hormone made by the ovaries.

Birth control — People with POI often experience intermittent ovarian function and occasional ovulation. This means pregnancy is unlikely but possible. If you wish to avoid pregnancy, you can take birth control pills rather than estradiol with progesterone. The pill contains higher doses of hormones that are necessary to prevent pregnancy.

Duration of estrogen therapy — Some people worry that hormone replacement therapy is not safe. However, studies in people with POI show that hormone therapy is safe and helps prevent future medical problems. People with POI are more likely to have cardiovascular problems if they don't take hormones than if they do. Plus, not taking hormones can lead to osteoporosis.

Experts agree that young people with POI should use hormone therapy at least until they turn 50, which is the average age of menopause.

Family planning — Between 5 and 10 percent of people with POI are able to conceive and carry a pregnancy without any special treatment. Treatment with estrogen, fertility drugs, or other hormones has not been shown to improve fertility in people with POI.

If you want to try to get pregnant, work with your health care provider to identify the cause of your condition before you start trying. Some chromosomal and genetic conditions can cause problems with a pregnancy or developing baby. For people who are not able to get pregnant naturally, one option is in vitro fertilization (IVF) with donor eggs (see "Patient education: In vitro fertilization (IVF) (Beyond the Basics)"). Some people choose to grow their family through adoption.

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Primary ovarian insufficiency (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Adrenal insufficiency (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Clinical manifestations and diagnosis of Turner syndrome
Evaluation and management of secondary amenorrhea
Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)
Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse
Management of primary ovarian insufficiency (premature ovarian failure)
Management of Turner syndrome in children and adolescents
Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)
Autoimmune primary ovarian insufficiency (premature ovarian failure)
Clinical manifestations of adrenal insufficiency in adults

The following organizations also provide reliable health information.

●National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)

●American Society for Reproductive Medicine

(www.asrm.org)

●Resolve: The National Infertility Association

(www.resolve.org)