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PRIMARY OVARIAN INSUFFICIENCY OVERVIEW — Primary ovarian insufficiency (POI) is a condition in which the ovaries spontaneously stop functioning normally in people who are younger than 40 years. It is also a type of "premature menopause."
Normally, menopause occurs between the ages of 45 and 55. However, in some people, it happens earlier. Doctors use the term "early menopause" for people who stop having monthly periods between age 40 and 45. The term "premature menopause" is used to describe menopause that happens before age 40. This can happen for different reasons; for example, chemotherapy or radiation therapy for cancer can impair ovarian function, or in some cases, the ovaries are removed (eg, to prevent or treat cancer), which causes "surgically induced" menopause. Sometimes, monthly periods stop before age 40 for no clear reason; when this happens, doctors refer to it as POI.
In people with POI, the ovaries:
●Stop releasing eggs, or release them only intermittently, and
●Stop producing the hormones estrogen, progesterone, and testosterone, or produce them only intermittently
Given these effects, POI makes pregnancy unlikely, although some people continue to have intermittent periods for some time, during which it may be possible to get pregnant. A diagnosis of POI can be emotionally devastating to many people, especially if they were planning to become pregnant in the future. If that is true for you, it's important to take time to heal emotionally and to learn about your options, which may include adoption, pregnancy with donor eggs, seeking a gestational carrier (surrogacy), and remaining childless.
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 or to participate in a professionally monitored support group for people with POI. If you have a partner, remember that they may also be affected by your diagnosis, so it might be useful to find help in processing related emotions for the two of you.
PRIMARY OVARIAN INSUFFICIENCY CAUSES — In the vast majority of cases, health care providers do not know why primary ovarian insufficiency (POI) 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. 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 abnormal 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. In Turner syndrome, females 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 just a portion of one X chromosome (a critical portion) can also cause POI.
●Fragile X syndrome – Fragile X syndrome is the most common cause of intellectual disability worldwide. People who have 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; hence, a person whose POI is caused by a change in the fragile X gene who is able to get pregnant is 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 undergo genetic counseling before trying to get pregnant.
●Other chromosomal and genetic causes – Several other chromosomal and genetic abnormalities can lead to POI. For example, some females have Y chromosome material, even though the Y chromosome should exist 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. (Chemotherapy drugs are also often used to treat diseases like severe rheumatoid arthritis.)
Autoimmune causes — The job of the body's 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 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 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). (See "Patient education: Adrenal insufficiency (Addison's disease) (Beyond the Basics)".)
PRIMARY OVARIAN INSUFFICIENCY SYMPTOMS — Most people with primary ovarian insufficiency (POI) undergo normal puberty and have regular periods before developing ovarian insufficiency. The most common symptom that prompts them to seek medical care is missed or infrequent periods.
Some people first notice that their periods are infrequent or absent when they stop taking birth control pills, but this does not mean that the pills caused POI. While taking the pill may mask the condition, it cannot cause it.
Other POI symptoms include hot flashes or vaginal dryness because the body eventually produces little or no estrogen. As the condition progresses, some people may also develop vaginal dryness and thinning of the vaginal walls, which can make sex painful.
Family planning — With POI, the ovaries eventually stop working, making it impossible to get pregnant naturally. Even so, between 5 and 10 percent of people with the condition are able to conceive and carry a pregnancy. Others become pregnant through in vitro fertilization (IVF) using donor eggs. (See 'Infertility treatment' below.)
PRIMARY OVARIAN INSUFFICIENCY 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, the condition can have implications for your overall health. People with primary ovarian insufficiency (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 light, irregular, or absent periods. 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, or received chemotherapy or radiation therapy, as these all damage ovarian tissue.
●You or any of your family members have any autoimmune diseases, such as polyglandular failure, hypothyroidism, Addison's 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 insufficiency.
●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 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.
●You have any hearing loss, because some genetic causes of POI can cause deafness.
Important tests — In addition to asking you detailed questions about your personal and family history and performing a physical examination, your health care provider should order a blood test to measure various hormone levels.
To be diagnosed with POI, 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.
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.)
PRIMARY OVARIAN INSUFFICIENCY TREATMENT
Self-care — The diagnosis is more than infertility and can affect both your physical and emotional well-being. Management of the condition must address both. Before deciding about your plans for a family, it is first important to be healthy yourself. There are multiple choices available to you if you decide you want to become a parent.
Estrogen replacement — One of the main goals of primary ovarian insufficiency (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. Estrogen therapy aims to prevent or relieve all of these consequences of estrogen deficiency. However, 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 cancer of the uterus. People who do not have a uterus (ie, have had a hysterectomy) can take estrogen alone.
Most experts currently recommend that people with POI should take estrogen until age 50 to 51 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 this type of estrogen best mimics the "natural condition," but other forms of estrogen are available and are also effective.
People who choose estradiol can get it in pill form, in a patch that is worn on the skin, or in a ring that is inserted into the vagina. The estradiol patch and vaginal ring may offer advantages over the pill form, including:
●They deliver the same hormone that the ovaries make
●The estrogen does not have to go through the liver to get into the bloodstream
●The estrogen gets into the body in a slow, steady stream, rather than all at once
●The estrogen can be measured easily in the bloodstream
Despite the advantages the patch and ring may have, other forms of estrogen replacement are also effective, and you should choose the form that best suits you. Some people do not like wearing the patch or using the ring; others develop skin irritation when they wear the patch. In these situations, hormones in pill form may be a better choice. In addition, oral estrogen is often less expensive than the estradiol patch or ring. Regardless of the form of estrogen you choose, you will likely also need to take some form of progestin (a type of progesterone). With progestins, you also have choices. They come in patch or pill form, and there are synthetic and "natural" versions.
People who wish to avoid pregnancy can take birth control pills. Low-dose hormone therapy does not prevent pregnancy. People with POI commonly experience unpredictable and intermittent ovarian function, and it is estimated that there is an approximate 4 percent chance of ovulating each month.
Duration of estrogen therapy — People taking estrogen and progestin may worry about the risks of hormone replacement therapy, as studies have linked the use of these hormones with an elevated risk of heart attack, stroke, and breast cancer, among other things. However, it's important to know that those studies looked at the effects of estrogen and progestin in people who were in their 60s and 70s and who had undergone menopause naturally.
The results of those studies do not apply to younger people with POI. On the contrary, studies in people 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 people with POI should use hormone therapy at least until they turn 50 years of age.
Infertility treatment — As noted above, between 5 and 10 percent of people with POI 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 (IVF) with donor eggs. In one report of 61 people with POI 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 want to try to get pregnant, work with your health care provider to identify the cause of your condition before you start trying. Some underlying causes of POI can cause problems with a pregnancy or a fetus, if a pregnancy is successful. In some situations, adoption is a good option.
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: Premature menopause (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 (Addison's disease) (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
Ovarian failure due to anticancer drugs and radiation
Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)
Clinical features and diagnosis of 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
●Resolve: The National Infertility Association
