Primary Ovarian Insufficiency (POI)

Primary ovarian insufficiency (POI) is the term used to describe when a woman’s ovaries stop working normally before she reaches the age of 40. POI is not the same as early or premature menopause. Many women with POI do not get monthly menstrual periods, or they have them irregularly. Problems with ovulation may make it difficult for women with POI to get pregnant. In addition, women with POI are at higher risk for certain health conditions, such as osteoporosis, than are women who do not have POI.

NICHD studies a range of issues related to POI, including possible causes of and mechanisms involved with POI, conditions associated with POI, and treatments and support for the physical and emotional health of women and families affected by POI.

About Primary Ovarian Insufficiency (POI)

What is POI?

Healthcare providers use the term POI when a woman's ovaries stop working normally before she is 40 years of age.1,2

Many women naturally experience reduced fertility when they are around 40 years old. This age may mark the start of irregular menstrual periods that signal the onset of menopause. For women with POI, irregular periods and reduced fertility occur before the age of 40, sometimes as early as the teenage years.3,4

In the past, POI used to be called "premature menopause" or "premature ovarian failure," but those terms do not accurately describe what happens in a woman with POI. A woman who has gone through menopause will never have another normal period and cannot get pregnant. A woman with POI may still have periods, even though they might not come regularly, and she may still get pregnant.2,4

Who is at risk?

Several factors can affect a woman's risk for POI:

  • Family history. Women who have a mother or sister with POI are more likely to have the disorder. About 10% to 20% of women with POI have a family history of the condition.5
  • Genes. Some changes to genes and genetic conditions put women at higher risk for POI. Research suggests that these disorders and conditions cause as much as 28% of POI cases.6 For example:
    • Women who carry a variation of the gene for Fragile X syndrome are at higher risk for Fragile X-Associated POI (FXPOI).7 Fragile X syndrome is the most common inherited form of intellectual and developmental disability, but women with FXPOI do not have Fragile X syndrome itself. Instead, they have a change or mutation in the same gene that causes Fragile X syndrome, and this change is linked to FXPOI. Visit the What is the connection between POI and Fragile X syndrome? section of the site for more information.
    • Most women who have Turner syndrome develop POI. Turner syndrome is a condition in which a girl or woman is partially or completely missing an X chromosome. Most women are XX, meaning they have two X chromosomes. Women with Turner syndrome are X0, meaning one of the X chromosomes is missing.
  • Other factors. Autoimmune diseases, viral infections, chemotherapy, and other treatments also may put a woman at higher risk of POI.5

Citations

  1. American Congress of Obstetricians and Gynecologists. (2009). Premature ovarian failure: ACOG medical student teaching module [PowerPoint slides]. Retrieved January 3, 2012, from https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2014/07/primary-ovarian-insufficiency-in-adolescents-and-young-women?utm_source=redirect&utm_medium=web&utm_campaign=otn external link
  2. National Library of Medicine, Medline Plus. (2011). Premature ovarian failure. Retrieved January 4, 2012, from https://medlineplus.gov/primaryovarianinsufficiency.html
  3. American College of Obstetricians and Gynecologists. (2011). Primary ovarian insufficiency in the adolescent external link : Committee opinion no. 502. Obstetrics and Gynecology, 118, 741–745.
  4. Nelson, L. M. (2009). Primary ovarian insufficiency. New England Journal of Medicine, 360, 606–614.
  5. Cordts, E. B., Christofolini, D. M., Dos Santos, A. A., Bianco, B., & Barbosa, C. P. (2011). Genetic aspects of premature ovarian failure: A literature review. Archives of Gynecology and Obstetrics, 283, 635–643.
  6. Fridovich-Keil, J. L., Gubbels, C. S., Spencer, J. B., Sanders, R. D., Land, J. A., & Rubio-Gozalbo, E. (2011). Ovarian function in girls and women with GALT-deficiency galactosemia. Journal of Inherited Metabolic Disease, 34, 357–366.
  7. Trans-NIH Fragile X Research Coordinating Group and Scientific Working Groups. (2008). National Institutes of Health research plan on Fragile X syndrome and associated disorders. Retrieved January 4, 2012, from https://www.nichd.nih.gov/sites/default/files/publications/pubs/Documents/nih_fragilex_research_plan_2009.pdf (PDF 439 KB)

What causes POI?

In most cases, the exact cause of POI is unknown.1,2,3

Research shows that POI is related to problems with the follicles—the small sacs in the ovaries in which eggs grow and mature.3

Follicles start out as microscopic seeds called primordial follicles. These seeds are not yet follicles, but they can grow into them. Normally, a woman is born with approximately 2 million primordial follicles,4 typically enough to last until she goes through natural menopause, usually around age 50.2

For a woman with POI, there are problems with the follicles:5

  • Follicle depletion. A woman with follicle depletion runs out of working follicles earlier than normal or expected. In the case of POI, the woman runs out of working follicles before natural menopause occurs around age 50. Presently there is no safe way for scientists today to make primordial follicles.
  • Follicle dysfunction. A woman with follicle dysfunction has follicles remaining in her ovaries, but the follicles are not working properly. Scientists do not have a safe and effective way to make follicles start working normally again.3

Although the exact cause is unknown in a majority of cases, some causes of follicle depletion and dysfunction have been identified:

  • Genetic and chromosomal disorders. Disorders such as Fragile X syndrome and Turner syndrome can cause follicle depletion.3,4,6
  • Low number of follicles. Some women are born with fewer primordial follicles, so they have a smaller pool of follicles to use throughout their lives. Even though only one mature follicle releases an egg each month, less mature follicles usually develop along with that mature follicle and egg. Scientists don't understand exactly why this happens, but these "supporting" follicles seem to help the mature follicle function normally. If these extra follicles are missing, the main follicle will not mature and release an egg properly.
  • Autoimmune diseases. Typically, the body's immune cells protect the body from invading bacteria and viruses. However, in autoimmune diseases, immune cells turn on healthy tissue. In the case of POI, the immune system may damage developing follicles in the ovaries. It could also damage the glands that make the hormones needed for the ovaries and follicles to work properly. Several studies suggest that about one-fifth of with POI have an autoimmune disease.2,7
    • Thyroiditis is the autoimmune disorder most commonly associated with POI.7 It is an inflammation of the thyroid gland, which makes hormones that control metabolism, or the pace of body processes.
    • Addison's disease is also associated with POI. Addison's disease affects the adrenal glands, which produce hormones that help the body respond to physical stress, such as illness and injury; the hormones also affect ovary function.8 A small percentage of women with POI have Addison's disease.
  • Chemotherapy or radiation therapy. These strong treatments for cancer may damage the genetic material in cells, including follicle cells.1,3
  • Metabolic disorders. These disorders affect the body's ability to create, store, and use the energy it needs. For example, galactosemia affects how your body processes galactose, a type of sugar. A majority of women with galactosemia also have POI.7
  • Toxins. Cigarette smoke, chemicals, and pesticides can speed up follicle depletion. In addition, viruses have been shown to affect follicle function.2,4

Citations

  1. 1. Kodaman, P. H. (2010). Early menopause: Primary ovarian insufficiency and surgical menopause. Seminars in Reproductive Medicine, 28, 360–369. https://pubmed.ncbi.nlm.nih.gov/20845236/
  2. Nelson, L. M. (2009). Primary ovarian insufficiency. New England Journal of Medicine, 360, 606–614. https://pubmed.ncbi.nlm.nih.gov/19196677/
  3. De Vos, M., Devroey, P., & Fauser, B. C. (2010). Primary ovarian insufficiency. Lancet, 376, 911–921. https://pubmed.ncbi.nlm.nih.gov/20708256/
  4. Welt, C. K. (2008). Primary ovarian insufficiency: A more accurate term for premature ovarian failure. Clinical Endocrinology, 68, 499–509. https://pubmed.ncbi.nlm.nih.gov/17970776/
  5. American Congress of Obstetricians and Gynecologists Committee Opinion of Primary Ovarian Insufficiency. https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2014/07/primary-ovarian-insufficiency-in-adolescents-and-young-women external link
  6. Cordts, E. B., Christofolini, D. M., Dos Santos, A. A., Bianco, B., & Barbosa, C. P. (2011). Genetic aspects of premature ovarian failure: A literature review. Archives of Gynecology and Obstetrics, 283, 635–643. https://pubmed.ncbi.nlm.nih.gov/21188402/
  7. Rebar, R. W. (2009). Premature ovarian failure. Obstetrics and Gynecology, 113, 1355–1363. https://pubmed.ncbi.nlm.nih.gov/19461434/
  8. National Center for Biotechnical Information. (2009). Addison's disease. Retrieved January 12, 2012, from https://medlineplus.gov/addisondisease.html

How do healthcare providers diagnose POI?

The key signs of POI are:

  • Missed or irregular periods for 4 months, typically after having had regular periods for a while
  • High levels of follicle-stimulating hormone (FSH)
  • Low levels of estrogen1,2,3

If a woman is younger than age 40 and begins having irregular periods or stops having periods for 4 months or longer, her healthcare provider may take these steps to diagnose the problem:

  • Do a pregnancy test. This test will rule out an unexpected pregnancy as the reason for missed periods.2
  • Do a physical exam. During the physical exam, the healthcare provider looks for signs of other disorders. In some cases, the presence of these other disorders will rule out POI. Or, if the other disorders are associated with POI, such as Addison's disease, a healthcare provider will know that POI may be present.2
  • Collect blood. The healthcare provider will collect your blood and send it to a lab, where a technician will run several tests, including:
    • Follicle-Stimulating Hormone (FSH) test. FSH signals the ovaries to make estrogen, sometimes called the "female hormone" because women need high levels of it for fertility and overall health. If the ovaries are not working properly, as is the case in POI, the level of FSH in the blood increases. The healthcare provider may do two FSH tests, at least a month apart. If the FSH level in both tests is as high as it is in women who have gone through menopause, then POI is likely.2
    • Luteinizing hormone (LH) test. LH signals a mature follicle to release an egg. Women with POI have high LH levels, more evidence that the follicles are not functioning normally.4
    • Estrogen test. In women with POI, estrogen levels are usually low, because the ovaries are not functioning properly in their role as estrogen producers.4
    • Karyotype test. This test looks at all 46 of your chromosomes to check for abnormalities. The karyotype test could reveal genetic changes in the structure of chromosomes that might be associated with POI and other health problems.2,4
  • Do a pelvic ultrasound. In this test, the healthcare provider uses a sound wave (sonogram) machine to create and view pictures of the inside of a woman's pelvic area. A sonogram can show whether or not the ovaries are enlarged or have multiple follicles.2,5

The healthcare provider will also ask questions about a woman's medical history. He or she may ask about:

  • A blood relative with POI or its symptoms
  • A blood relative with Fragile X syndrome or an unidentified intellectual or developmental disability
  • Ovarian surgery
  • Radiation or chemotherapy treatment
  • Pelvic Inflammatory Disease or other sexually transmitted infections
  • An endocrine disorder, such as diabetes2

If they do not do tests to rule out POI, some healthcare providers might assume missed periods are related to stress.2 However, this approach is problematic because it will lead to a delay in diagnosis; further evaluation is needed.2

Citations

  1. De Vos, M., Devroey, P., & Fauser, B. C. (2010). Primary ovarian insufficiency. Lancet, 376, 911–921.
  2. Nelson, L. M. (2009). Primary ovarian insufficiency. New England Journal of Medicine, 360, 606–614.
  3. Rebar, R. W. (2009). Premature ovarian failure. Obstetrics and Gynecology, 113(6), 1355–1363.
  4. American Congress of Obstetricians and Gynecologists. (2009). Premature ovarian failure. ACOG medical student teaching module [PowerPoint slides]. Retrieved January 3, 2012, from https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2014/07/primary-ovarian-insufficiency-in-adolescents-and-young-women?utm_source=redirect&utm_medium=web&utm_campaign=otn external link
  5. Kodaman, P. H. (2010). Early menopause: Primary ovarian insufficiency and surgical menopause. Seminars in Reproductive Medicine, 28, 360–369.

Are there disorders or conditions associated with POI?

Because POI results in lower levels of certain hormones, women with POI are at greater risk for a number of health conditions, including:

  • Osteoporosis. The hormone estrogen helps keep bones strong. Without enough estrogen, women with POI often develop osteoporosis. Osteoporosis is a bone disease that causes weak, brittle bones that are more likely to break and fracture.1
  • Low thyroid function. This problem also is called hypothyroidism. The thyroid is a gland that makes hormones that control your body’s metabolism and energy level. Low levels of the hormones made by the thyroid can affect your metabolism and can cause very low energy and mental sluggishness. Cold feet and constipation are also features of low thyroid function. Some women with POI also have low thyroid function.2
  • Anxiety and depression. Hormonal changes caused by POI can contribute to anxiety or lead to depression.3 Women diagnosed with POI can be shy, anxious in social settings, and may have low self-esteem more often than women without POI.2 It is possible that depression may contribute to POI.3
  • Cardiovascular (heart) disease. Lower levels of estrogen, as seen in POI, can affect the muscles lining the arteries and can increase the buildup of cholesterol in the arteries. Both factors increase the risk of atherosclerosis—or hardening of the arteries—which can slow or block the flow of blood to the heart. Women with POI have higher rates of illness and death from heart disease than do women without POI.1,4,5
  • Dry eye syndrome and ocular (eye) surface disease. Some women with POI have one of these conditions, which cause discomfort and may lead to blurred vision.2 If not treated, these conditions can cause permanent eye damage.

Addison’s disease is also associated with POI. Addison’s disease is a life-threatening condition that affects the adrenal glands, which produce hormones that help the body respond to physical stress, such as illness and injury. These hormones also affect ovary function.6 A small percentage of women with POI have Addison's disease.7

Citations

  1. American Congress of Obstetricians and Gynecologists. (2009). Premature ovarian failure. ACOG medical student teaching module [PowerPoint slides]. Retrieved January 3, 2012, from https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2014/07/primary-ovarian-insufficiency-in-adolescents-and-young-women?utm_source=redirect&utm_medium=web&utm_campaign=otn external link
  2. Nelson, L. M. (2009). Primary ovarian insufficiency. New England Journal of Medicine, 360, 606–614.
  3. Schmidt, P. J., Luff, J. A., Haq, N. A., Vanderhoof, V. H., Koziol, D. E., Calis, K. A., et al. (2011). Depression in women with spontaneous 46, XX primary ovarian insufficiency. Journal of Clinical Endocrinology & Metabolism, 96, E278–E287.
  4. De Vos, M., Devroey, P., & Fauser, B. C. (2010). Primary ovarian insufficiency. Lancet, 376, 911–921.
  5. Kodaman, P. H. (2010). Early menopause: Primary ovarian insufficiency and surgical menopause. Seminars in Reproductive Medicine, 28, 360–369.
  6. National Center for Biotechnical Information, PubMed Health. (2009). Addison’s disease.
  7. Eunice Kennedy Shriver National Institute of Child Health and Human Development. (2007). Premature ovarian failure. Retrieved January 4, 2012, from http://www.nichd.nih.gov/health/topics/poi

What are the treatments for POI?

Currently, there is no proven treatment to restore normal function to a woman's ovaries.1,2 But there are treatments for some of the symptoms of POI, as well as treatments and behaviors to reduce health risks and conditions associated with POI.

It is also important to note that between 5% and 10% of women with POI get pregnant without medical intervention after they are diagnosed with POI.3 Some research suggests that these women go into what is known as "spontaneous remission" of POI, meaning that the ovaries begin to function normally on their own. When the ovaries are working properly, fertility is restored and the women can get pregnant.3

Select one of the following topics to learn more about common treatments for POI and its associated conditions.

HRT is the most common treatment for women with POI. It gives the body the estrogen and other hormones that the ovaries are not making. HRT improves sexual health and decreases the risks for cardiovascular disease (including heart attacks, stroke, and high blood pressure) and osteoporosis.4

If a woman with POI begins HRT, she is expected to start having regular periods again. In addition, HRT is expected to reduce other symptoms, such as hot flashes and night sweats, and help maintain bone health.1,5,6,7 HRT will not prevent pregnancy, and evidence suggests it might improve pregnancy rates for women with POI by lowering high levels of luteinizing hormone — which stimulates ovulation — to normal in some women.8

HRT is usually a combination of an estrogen and a progestin. A progestin is a form of progesterone. Sometimes, the combination might also include testosterone, although this approach is controversial.9 HRT comes in several forms: pills, creams, gels, patches that stick onto the skin, an intrauterine device, or a vaginal ring.10 Estradiol is the natural form of human estrogen. The optimal method of providing estradiol to women with POI is by a skin patch or vaginal ring. These methods are linked with a lower risk of potentially fatal blood clots developing. Most women require a dose of 100 micrograms of estradiol per day. It is important to take a progestin along with estradiol to balance out the effect of estrogen on the lining of the womb. Women who do not take a progestin along with estradiol are at increased risk of developing endometrial cancer. The progestin with the best evidence available to support use in women with POI is 10 mg of medroxyprogesterone acetate by mouth per day for the first 12 calendar days of each month.

A healthcare provider may suggest that a woman with POI take HRT until she is about 50 years old, the age at which menopause usually begins.

After that time, she should talk with her healthcare provider about stopping the treatment because of risks associated with using this type of therapy in the years after the normal age of menopause.3

In general, HRT treatment for women with POI is safe and is associated with only minimal side effects. Women with POI take HRT to replace hormones their bodies would normally be making if they didn't have POI.

The HRT taken by women with POI is different from the hormone therapies taken by women who are going through or have gone through natural menopause, which are often called menopausal or post-menopausal hormone therapy (PMHT).

A large, long-term study—called the Women's Health Initiative—examined the effects of a specific type of PMHT, taken for more than 5 years, by women ages 50 to 79 who had already gone through menopause. This study showed that PMHT was associated with an increased risk of stroke, blood clots, heart disease, heart attacks, and breast cancer in these women.11

These results do not apply to young women with POI who take HRT.3,10 The type and amount of HRT prescribed to women with POI is different from the PMHT taken by older women.3

A woman should talk to her healthcare provider if she has questions about HRT as a treatment for POI. Also, she should tell her healthcare provider about any side effects she experiences while taking HRT. There are many different types of HRT. Women should work with their healthcare providers to find out the best type of treatment.

Because women with POI are at higher risk for osteoporosis, they should get at least 1,200 to 1,500 mg of elemental calcium and 1000 IU (international units) of vitamin D, which helps the body absorb calcium, every day.12 These nutrients are important for bone health.10 A healthcare provider may do a bone mineral density test to check for bone loss.8

Weight-bearing physical activity, such as walking, jogging, and stair climbing, helps build bone strength and prevents osteoporosis.10 Maintaining a healthy body weight and getting regular physical activity are also important for reducing the risk of heart disease. These factors can affect cholesterol levels, which in turn can change the risk for heart disease.13

POI is associated with other health conditions, including (but not limited to) Addison's disease, Fragile X permutation, thyroid dysfunction, depression, anxiety, and certain other genetic, metabolic, and autoimmune disorders.

Women who have POI as well as one of these associated conditions will require additional treatment for the associated condition. In some cases, treatment involves medication or hormone therapy. Other types of treatments might also be needed.

For many women who experience infertility, including those with POI, feelings of loss are common. In one study, almost 9 out of 10 women reported feeling moderate to severe emotional distress when they learned of their POI diagnosis.10,14 Several organizations offer help finding these types of professionals. Visit the Resources and Publications section for more information.

Receiving a diagnosis of POI can be emotionally difficult for teenagers and their parents. A teen may have a similar emotional experience as an adult who receives the diagnosis, but there are many aspects of the experience that are unique to being a teenager.16 It is important for parents, the teenager, and healthcare providers to work closely together to ensure that the teenager gets the right treatment and maintains her emotional and physical health in the long term. There are resources to provide advice and support for parents, teenagers, and healthcare providers. Visit the Resources and Publications section for more information.

Citations

  1. American Congress of Obstetricians and Gynecologists. (2009). Premature ovarian failure. ACOG medical student teaching module [PowerPoint slides].
  2. National Library of Medicine. (2011). Premature ovarian failure. Retrieved January 4, 2012, from https://medlineplus.gov/primaryovarianinsufficiency.html
  3. Nelson, L. M. (2009). Primary ovarian insufficiency. New England Journal of Medicine, 360, 606–6.
  4. Shelling, A. N. (2010). Premature ovarian failure. Reproduction, 140, 633-641.
  5. Fridovich-Keil, J. L., Gubbels, C. S., Spencer, J. B., Sanders, R. D., Land, J. A., & Rubio-Gozalbo, E. (2011). Ovarian function in girls and women with GALT-deficiency galactosemia. Journal of Inherited Metabolic Disease, 34, 357–366.
  6. National Institutes of Health. (2010). Too young for hot flashes? When menopause-like symptoms come too soon. NIH News in Health. Retrieved January 4, 2012, from  https://newsinhealth.nih.gov/2010/06/too-young-hot-flashes
  7. Rebar, R. W. (2009). Premature ovarian failure. Obstetrics and Gynecology, 113(6), 1355–1363.
  8. Popat, V.B., Vanderhoof, V.H., Calis, K.A., Troendle, J.F., & Nelson, L.M. (2008). Normalization of serum lutenizing hormone levels in women with 46,XX spontaneous primary ovarian insufficiency. Fertility and Sterility, 89(2), 429-433
  9. Kodaman, P. H. (2010). Early menopause: Primary ovarian insufficiency and surgical menopause. Seminars in Reproductive Medicine, 28, 360–369.
  10. National Library of Medicine, MedlinePlus. (2010). Estrogen vaginal. Retrieved February 24, 2012, from https://medlineplus.gov/druginfo/meds/a606005.html
  11. NHLBI. (n.d.). Women's Health Initiative background and overview. Retrieved January 4, 2012, from https://www.nhlbi.nih.gov/science/womens-health-initiative-whi
  12. Institute of Medicine of the National Academies. (2010). DRIs for calcium and vitamin D. Retrieved February 25, 2012, from https://www.nap.edu/resource/13050/Vitamin-D-and-Calcium-2010-Report-Brief.pdf external link (PDF 320 KB)
  13. National Heart, Lung, and Blood Institute. (2009). At-a-glance: What you need to know about high blood cholesterol. Retrieved May 23, 2012, from https://www.nhlbi.nih.gov/resources/cholesterol-your-heart-what-you-need-know (PDF 2.15 MB)
  14. Groff, A. A., Covington, S. N., Halverson, L. R., Fitzgerald, O. R., Vanderhoof, V., Calis, K., et al. (2005). Assessing the emotional needs of women with spontaneous premature ovarian failure. Fertility and Sterility, 83, 1734–1741.
  15. Ventura, J. L., Fitzgerald, O. R., Koziol, D. E., Covington, S. N., Vanderhoof, V. H., Calis, K. A., et al. (2007). Functional well-being is positively correlated with spiritual well-being in women who have spontaneous premature ovarian failure. Fertility and Sterility ;87: 584–590.
  16. Covington, S. N., Hillard, P. J., Sterling, E. W., Nelson, L. M., & POI Recovery Group. (2011). A family systems approach to primary ovarian insufficiency. Journal of Pediatric and Adolescent Gynecology, 24, 137–141.
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