Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

What is FXPOI?

FXPOI is the term used to describe a loss of normal function of the ovaries before the age of 40 in women who have a certain type of change called a premutation in their FMR1 gene located on the X chromosome.

People who have what's called a full mutation in the FMR1 gene (instead of the premutation) are likely to have Fragile X syndrome, the most common inherited form of intellectual and developmental disabilities (IDDs). People with the premutation usually do not have IDDs, but they may have some learning disabilities. Or, they may not have any IDD-related features.^1,2

Studies suggest that there may be a wide spectrum of ovarian dysfunction among women who are premutation carriers, with premature ovarian insufficiency being the most extreme.³ Studies have shown that between 12 percent and 28 percent of women who are fragile X premutation carriers have primary ovarian insufficiency.⁴ Most women with FXPOI have irregular menstrual periods and experience problems with fertility. They may have symptoms that are similar to those of menopause, such as hot flashes, night sweats, and vaginal dryness. Some women with FXPOI go through menopause as early as age 40 or even younger.⁵

The exact number of people with the FMR1 premutation is not known. And only a portion of women with the premutation will also have FXPOI.

For more information about the genetics of Fragile X-associated disorders, please consult the section explaining how genes cause Fragile X-associated disorders.

Women who have a premutation in the FMR1 gene are at risk of having premature ovarian insufficiency, a condition called FXPOI. Scientists believe that the altered FMR1 gene may create byproducts that are toxic to cells in the ovaries, altering their normal function, causing infertility and menopause-like symptoms.^1,2,3 Alternatively, the premutation may cause the FMR1 gene to produce a protein that interferes with fertility.³

Not all women with the FMR1 premutation develop FXPOI. Researchers do not yet understand why some women develop the condition and others do not.

Research has shown that smoking decreases the reproductive lifespan of women who are premutation carriers by about 1 year.⁴ Women with the premutation who might want to have children should avoid smoking in order to maximize their fertility lifespan and increase the chance that they can become pregnant.

Fragile X syndrome and its associated conditions are caused by mutations, or changes, in the FMR1 gene. The mutation affects how the gene functions in making a specific protein called FMRP.

On a gene, the information for making a protein has two parts: the introduction and the instructions for making the protein itself. Researchers call the introduction the promoter because of how it helps start the process of building the protein.

The promoter part of the FMR1 gene normally includes many repeats—repeated instances of a trio of DNA bases called a triplet repeat—in this case, many copies of the CGG triplet repeat—to help build the protein.

The number of repeats in the promoter varies from person to person.

• People who do not have the FMR1 triplet repeat expansion usually have between 6 and 40 repeats in the promoter; the average is 30 repeats.
• People whose FMR1 gene has between 55 and 200 repeats have a premutation.
• People whose FMR1 gene has more than 200 repeats have a full mutation.

Effects of Premutations Versus Full Mutations

Premutations and full mutations in the promoter region of the FMR1 gene can have different effects.

Premutations can cause specific disorders taht aren't found in people with the full mutation:

• Women with a premutation may have Fragile X-associated primary ovarian insufficiency (FXPOI).²
• People with a premutation may also have Fragile X-associated tremor and ataxia syndrome.¹

The number of repeats in the promoter region also affects the severity of a person's symptoms of Fragile X syndrome:

• People with a premutation may have milder symptoms of Fragile X syndrome, or they may have no symptoms at all.³
• People with a full mutation are more likely to have intellectual and developmental disabilities and other symptoms of Fragile X syndrome.³

Parents who have a FMR1 premutation may have no symptoms but still pass along the premutation to their children. That means their children could have Fragile X-associated disorders, including FXPOI. Also, the premutation can expand when it's passed along, so that a child of a parent with a premutation could have Fragile X syndrome.

FXPOI causes symptoms similar to other types of ovarian insufficiency.¹ These symptoms can include:

• Irregular menstrual periods (meaning that they may be infrequent, absent, or unusually light)
• Unusually short (less than 21 days) or long (more than 35 days) menstrual cycles
• Infertility—problems conceiving and/or carrying a pregnancy to term
• Symptoms of menopause, such as hot flashes, night sweats, and vaginal dryness
• Early menopause, sometimes before age 40—or even younger.¹

Women who are concerned that they might have FXPOI can get their levels of follicle-stimulating hormone (FSH) tested. FSH levels are higher in women whose ovaries are not working properly, compared with other women of the same age whose ovaries are functioning normally.¹

Healthcare providers may suggest genetic testing for a person who has a family history of Fragile X syndrome, infertility, or early menopause. Testing can help explain why a person is experiencing certain symptoms, such as irregular menstrual cycles, and can determine if a person is more likely to have a child with a Fragile X-associated disorder.

Prenatal Testing (During Pregnancy)

A pregnant woman who has the FMR1 premutation or full mutation may have a prenatal test to check the developing fetus for the mutated gene. This important information helps families and providers to prepare for Fragile X syndrome and to intervene as early as possible.

Possible types of prenatal tests include:

• Amniocentesis. A healthcare provider takes a sample of amniotic (pronounced am-nee-OT-ik) fluid, which is then tested for the FMR1 mutation.
• Chorionic villus sampling. A healthcare provider takes a sample of cells from the placenta, which is then tested for the FMR1 mutation.²

Because prenatal testing involves some risk to the mother and fetus, if you or a family member is considering prenatal testing, discuss all the risks and benefits with your healthcare provider.

According to the National Fragile X Foundation , testing can cost between about $300 and $600. Health insurance generally covers the cost if the test is considered medically necessary, either to diagnose a Fragile X-associated condition or to counsel a woman who is pregnant or plans to become pregnant. If you are considering Fragile X testing, check with your insurance company to find out if the testing is covered.¹

Although there are treatments for some of the symptoms of FXPOI, such as hot flashes, there is currently no treatment to cure or reverse infertility related to FXPOI. However, assisted reproductive technology can help some women with FXPOI become pregnant. Also, quitting smoking might help increase the fertility lifespan of women who are premutation carriers.¹

To learn more about treatments, select a link below.

• Treatments for FXPOI-related infertility
• Treatments for other FXPOI signs and symptoms

Keep in mind that women with an FMR1 premutation can pass the altered form of the gene to their children. There is also a risk that the premutation will expand to a full mutation when it is transmitted.² If this occurs, the child will have Fragile X syndrome.

Women who know they have an FMRI premutation can get genetic counseling before they get pregnant. A genetic counselor can provide information on the FMR1 premutation, the risks of passing the premutation to the child, or the possibility that an expansion to the full mutation might occur.

Infertility is a primary symptom of FXPOI. In fact, some women might not know they have an FMR1 premutation until they have trouble getting pregnant.

Currently no proven treatment will restore normal function to a woman's ovaries if she has FXPOI. In addition, research has shown that some fertility treatments are ineffective for women with FXPOI. Healthcare providers recommend avoiding unproven and ineffective fertility treatments because they may reduce a woman's chances of getting pregnant naturally.

Some women with FXPOI can and do get pregnant naturally. Younger women who are premutation carriers are similar to noncarriers with respect to their follicle-stimulating hormone levels.¹ This suggests that women with the premutation should not have significant FMR1-related fertility problems in their younger reproductive years. Because premutation-carrier women will have a shortened reproductive life span, it is important that they receive pre-pregnancy counseling so that they can incorporate this information into their family planning.¹

Healthcare providers usually recommend that a woman and her partner try to get pregnant naturally for at least 1 year before trying alternative methods. In women with FXPOI, healthcare providers might recommend trying for a longer period of time to promote natural pregnancy.

Other women with FXPOI might not be able to get pregnant naturally. These women and their families should discuss all the options for having a family with their healthcare provider.

Some women who don't get pregnant naturally might want to try assisted reproductive technologies (ART), such as in vitro fertilization, to get pregnant. ART does not guarantee pregnancy, and many forms of ART carry their own risks, some of them serious. In addition, ART may not be covered by standard insurance plans, and the methods can be costly. Women and families who are considering ART should discuss all the risks, benefits, and costs with their healthcare provider before making a final decision. The discussion should include the risk of passing on the premutation to their child, as well as the possibility that the premutation could expand to the full mutation, causing Fragile X syndrome in the child.

Others with FXPOI might consider adoption as a way to build their family. Adoption can be very rewarding, but the process is not without risks. Healthcare providers often recommend that families who are considering adoption learn about all of the risks and benefits of adoption and the adoption process before starting down the adoption path. There are legal, financial, and emotional issues to consider with adoption. Visit the Resources section for more information on adoption.

There are several effective treatments for some of the other symptoms of FXPOI, such as those related to menopause—hot flashes, night sweats, vaginal dryness, irritability, and poor concentration.

In many cases, healthcare providers will recommend hormone replacement therapy (HRT) to treat menopause symptoms in women with FXPOI. HRT provides the estrogen and other hormones that might be low or missing in women with FXPOI because their ovaries aren’t functioning properly. HRT might help to regulate menstrual cycles, which can make periods more regular, even out hormone levels, and reduce or slow bone loss, a common feature of low estrogen.

Is HRT safe for me to take if I have FXPOI?

HRT for women who have not gone through natural menopause—including women with FXPOI—simply replaces the hormones the body should be making on its own. This HRT is different from the HRT taken by women who are going through or have gone through natural menopause—sometimes called postmenopausal HRT.

Studies show that taking postmenopausal HRT to treat symptoms of menopause, especially for long periods of time, increases the risk of several health conditions. But these findings do not apply to women who have not gone through natural menopause.

Postmenopausal HRT extends the amount of time that a normal level of estrogen is available to the body, but HRT for women with FXPOI actually replaces the hormones that the body would be making if the ovaries were functioning properly.¹

If you have questions about the possible benefits and risks of HRT, talk with your healthcare provider.