Guide to primary ovarian insufficiency

Primary ovarian insufficiency (POI), formerly referred to as premature ovarian failure, is a condition in which the ovaries stop functioning normally in women and menstruating people who are under 40 years old.

POI is a disorder that can lead to infertility and premature menopause due to the ovaries being unable to produce enough eggs, and its hormonal implications can increase risk for other health risks as well.

Whether you were diagnosed with POI years ago or just yesterday, this condition can be a very difficult thing to learn about your body. This article is intended to explain more about what POI is and what you can do about it. 

Read on to learn: 

• What is primary ovarian insufficiency, or POI? Is it the same thing as premature menopause?
• What causes POI?
• What are the warning signs of POI?
• What are the fertility implications of POI? Can I still have children if I have this condition? 
• What are the long-term health risks to be aware of if I have POI?

What is primary ovarian insufficiency?

As mentioned above, primary ovarian insufficiency (POI) is a condition in which the ovaries stop functioning normally in menstruating people who are under 40 years old. It affects 0.5 - 3% of menstruating people in their reproductive years (1). POI is usually caused by a problem with one’s ovarian follicles, which are the structures in the ovaries that contain and release the eggs. The ovaries may run out of eggs prematurely, or the eggs may not develop properly.

While POI can lead to premature menopause, or menopause before the age of 40, it should be noted that it differs from menopause as roughly 50% of individuals still experience sporadic ovarian function (2).

Primary ovarian insufficiency (POI) can be classified into two main types: isolated POI and syndromic POI:

• Isolated POI refers to cases of POI where the condition occurs as an isolated entity, with no other associated symptoms or known medical conditions. ‍
• Syndromic POI refers to cases of POI where the condition occurs as part of a broader syndrome or medical condition. These conditions can include autoimmune disorders, genetic syndromes, or other medical conditions that affect multiple organ systems. Examples of syndromic POI include Turner syndrome, Fragile X syndrome, and galactosemia. In these cases, POI is just one of the many symptoms or complications associated with the broader condition.

Is POI the same thing as premature menopause?

Premature menopause is defined as menopause, or the cessation of periods, that occurs before the age of 40.

Although they share some similarities in symptoms and future health implications, POI and premature menopause are not the same condition. In POI, spontaneous ovulation can still happen, whereas with premature menopause, by definition, all ovulation and menses have stopped. 

However, POI can cause premature menopause. 

What causes POI? 

Frustratingly, the exact cause of POI is not always known, but it can be caused by a variety of factors such as autoimmune disorders, genetics, chemotherapy, radiation, and other medical treatments. Let's take a closer look at each of these potential causes.

Autoimmune conditions  

Several autoimmune disorders, conditions in which the body’s own immune system mistakenly attacks its own tissues, have been associated with the development of POI. Some of the autoimmune disorders that can cause POI include (3,4,5,6,7):

• Hashimoto's thyroiditis: This is a condition where the immune system attacks the thyroid gland, leading to an underactive thyroid. Women with Hashimoto's thyroiditis have an increased risk of developing POI.
• Addison's disease: This is a disorder where the adrenal glands do not produce enough hormones. People with Addison's disease may also have autoimmune antibodies that can attack the ovaries.
• Type 1 diabetes: Individuals with type 1 diabetes have an increased risk of developing POI, possibly due to the autoimmune nature of the disease.
• Systemic lupus erythematosus (SLE): This is an autoimmune disorder that can cause inflammation and damage to various organs in the body, including the ovaries.
• Antiphospholipid syndrome: This is a disorder where the immune system produces antibodies that can cause blood clots. Women with this syndrome may also experience ovarian failure.

It's important to note that not all people with autoimmune disorders will develop POI, and not all cases of POI are caused by autoimmune disorders. The exact cause of POI can be difficult to determine in some cases.

Note: There is also a potential link between infections that have an autoimmune component and POI that is sometimes discussed. For example, some case reports of Lyme disease have suggested a potential link between this infection, the chronic inflammation and autoimmune response it often triggers, and POI. It should be noted there is limited research on this topic, though, and while bacterial and viral infections can temporarily disrupt the menstrual cycle, it often regulates itself after some period of time. Be sure to talk with your doctor if you were recently sick and your menstrual cycle has not returned to normal. 

Genetic factors 

There is also a genetic component of POI: if your mother or someone in your close family had this condition, it is more likely that you will have it also. It is estimated that genetic factors account for 20-25% of POI cases (2).

As noted above, POI is associated with several genetic disorders like Turner syndrome, Fragile X syndrome, and galactosemia. However, research still indicates even for people without these conditions, there is a genetic link.  Let’s look at some of the research: 

• Some genes have been identified that may impact follicle development and steroid hormone biosynthesis (7).
• Several studies that have delved into understanding the genetic causes of POI have identified chromosomal abnormalities, single-gene mutations, and polygenic risk factors (8, 9).
• Specific variants in pleiotropic genes, or single genes that control more than 1 trait, may result in isolated POI rather than syndromic POI, whereas oligogenic defects (i.e., genetic disorders that result from two or more genes) might intensify the severity of POI symptoms and manifestation (10). 

Medical treatments 

Medical treatments like chemotherapy and radiation can cause damage to the ovaries, leading to primary ovarian insufficiency (POI). These treatments can cause DNA damage in the ovarian follicles, which can reduce the number of follicles and the pool of eggs in the ovaries.

Other medical treatments that may cause POI include surgeries that remove or damage the ovaries, such as oophorectomy or ovarian torsion. Certain medications, such as gonadotropin-releasing hormone agonists (GnRHa), which are sometimes used to treat endometriosis or uterine fibroids, can also cause temporary ovarian suppression or induce POI in some women.

It's important to discuss the potential risks and benefits of any medical treatments with your healthcare provider, especially if you are concerned about the impact on your ovarian function and fertility.

POI symptoms: Warning signs to look out for

POI is oftentimes not diagnosed until the ovaries have lost a great deal of their function. This is not ideal, as earlier detection would allow people more time to decide if they want to pursue any preventative fertility treatments like egg freezing or in-vitro fertilization (IVF) and would also enable people to begin hormone therapy earlier to minimize undesirable symptoms and long-term health impacts.

The symptoms of primary ovarian insufficiency (POI) can vary among individuals, but they often include:

1. Irregular or missed periods: One of the most common symptoms of POI is changes in menstrual cycles, such as missed periods or irregular cycles.
2. Short follicular phase: The first half of the menstrual cycle, from the start of menstruation until ovulation, is typically 14 days. If it is <11 days, it is considered a short follicular phase. This can be a symptom of primary ovarian insufficiency (POI), as it may indicate a decline in ovarian function and a decrease in estrogen production. However, a short follicular phase can also be caused by other factors, such as stress, poor nutrition, or certain medications.
3. Out-of-range hormones: High follicle stimulating hormone (FSH), low anti-mullerian hormone (AMH), and low estrogen are all indicators of POI. More information on these hormones’ specific functions can be found below.  
4. Hot flashes: Women with POI may experience hot flashes, which are sudden feelings of warmth and sweating, particularly at night.
5. Vaginal dryness: POI can lead to a decrease in estrogen levels, which can cause vaginal dryness and discomfort during intercourse.
6. Mood changes: Some women with POI may experience mood changes, such as depression, anxiety, or irritability.
7. Decreased sex drive: POI can also lead to a decreased sex drive or libido.
8. Infertility: POI can cause infertility, as the ovaries may not be able to release a healthy egg for fertilization.

It's important to note that some women with POI may not experience any symptoms initially, and the condition may be discovered during routine blood tests or when attempting to conceive. If you are experiencing any of these symptoms or have concerns about your reproductive health, it's important to speak with your healthcare provider for an evaluation and diagnosis.

How is POI diagnosed? 

POI is typically diagnosed based on a combination of clinical symptoms and laboratory testing. A healthcare provider will take a medical history, perform a physical exam, and order blood tests to evaluate hormone levels.

The following tests may be used to diagnose POI:

• Follicle-stimulating hormone (FSH) test: This blood test measures the level of FSH, which is a hormone that stimulates the growth of ovarian follicles (which contain eggs). In people with POI, FSH levels are often higher than normal because the ovaries are not responding to the hormone properly. It varies from provider to provider, but levels of over 20-30 mIU/mL are typically cause for concern (it is recommended that at least 2 readings of FSH are taken at least 1 month apart). 
• Estradiol test: This blood test measures the level of estradiol, which is a form of estrogen produced by the ovaries. In people with POI, estradiol levels may be lower than normal because the ovaries are not producing enough of this hormone. Like FSH, two readings of estrogen should be taken at least 1 month apart. Readings of lower than 20-50 pg/mL are a flag for POI. 
• Anti-Mullerian hormone (AMH) test: This blood test measures the level of AMH, which is a hormone produced by the developing follicles in the ovaries. People with POI may have low AMH levels because the follicles are not developing properly. “Normal” AMH levels are typically 1.5 - 4 ng/ml. An AMH of <1 ng/ml may predict poor ovarian reserve. 
• Karyotype test: This blood test can help to identify any chromosomal abnormalities that may be causing POI
• Imaging tests: An ultrasound or MRI may be used to visualize the ovaries and look for any structural abnormalities or signs of damage.

It's important to note that the diagnostic process for POI can be complex, and it may take time to fully evaluate and diagnose the condition. If you are concerned about your reproductive health or have symptoms of POI, it's best to consult with a healthcare provider for an evaluation and appropriate management.

Fertility implications of POI

POI is associated with infertility, as it can lead to a decline in the number and quality of ovarian follicles, which are necessary for ovulation and conception. People with POI may have difficulty getting pregnant naturally, and may require fertility treatments such as in vitro fertilization (IVF) or donor egg or embryo options to conceive.

It's important to note that the likelihood of conceiving with POI varies depending on individual factors, such as age, ovarian reserve, and response to treatment. In fact, as noted above, 5 - 10% of people with POI are able to conceive due to spontaneous ovulation. 

People with POI who are interested in having children may wish to consult with a reproductive endocrinologist, who can provide guidance on their fertility options and help develop a personalized treatment plan.

IVF and POI

Part of the reason of why it is so important to identify POI early is that if it is diagnosed when a person is still ovulating at some frequency and still has several ovarian follicles, fertility interventions like egg freezing and IVF have been shown to be more effective. 

Many factors impact whether IVF is successful for people with POI. Generally, it is important to understand that the success rates for IVF in people with POI who are using their own eggs are lower than the overall population. That is why using donor eggs is a common alternative path that many individuals with this condition do pursue.

What is the donor egg process like?

If POI is not identified until a person has already stopped ovulating, it is more likely that their body will be unresponsive to fertility treatment. However, most people with POI are still fully capable of carrying a pregnancy with a donor egg in conjunction with IVF. 

In this process, eggs are retrieved from a donor (who has normal ovarian function), and fertilized with sperm from the recipient's partner or a donor sperm. The resulting embryos are then transferred to the recipient's uterus.

The process of using donor eggs typically involves several steps:

1. Finding a donor: This can be done through a fertility clinic or an agency that specializes in egg donation. Donors are usually young women between the ages of 21 and 34 who have undergone a thorough screening process to ensure they are healthy and have good reproductive potential.
2. Synchronizing the menstrual cycles: The recipient's menstrual cycle is synchronized with the donor's cycle using medications, so that the recipient's uterus is ready to receive the embryos when they are ready. This process typically takes 6-8 weeks.
3. Fertilization: The donor's eggs are retrieved and fertilized with sperm in the lab. The resulting embryos are then cultured for several days.
4. Embryo transfer: The embryos are transferred to the recipient's uterus via a thin catheter. The number of embryos transferred depends on factors such as the age of the donor and the recipient's preferences. Any additional viable embryos can be frozen for later use.
5. Pregnancy test: About two weeks after the embryo transfer, a pregnancy test is performed to determine if the treatment was successful.

Donor egg IVF has a high success rate, with some studies reporting success rates of over 50% per cycle (11, 12). However, it can be expensive and may not be covered by insurance. Additionally, it can be an emotionally complex process, as it involves using genetic material from a donor. It's important for individuals and couples considering donor egg IVF to discuss their feelings and concerns with their healthcare provider and seek counseling if needed.

Other POI health concerns 

Beyond its often-discussed fertility implications, POI can also put people at risk of developing a host of other health issues such as osteoporosis, cardiovascular disease, and depression.

This is largely because of the hormonal implications of the ovaries not functioning optimally, particularly estrogen. Estrogen has many functions in the body beyond just regulating the menstrual cycle and fertility. It plays a role in bone health, cardiovascular health, and mood regulation.

Let’s look at how estrogen and the loss of other female hormones impacts our bone health, heart health, and mental health: 

• Bone health: Without estrogen, women with POI are at increased risk for osteoporosis, a condition characterized by weak and brittle bones. Estrogen helps to keep bones strong by regulating the activity of bone cells called osteoblasts and osteoclasts. Without estrogen, the balance between these cells is disrupted, leading to bone loss and an increased risk of fractures.
• Heart health: Estrogen also plays a role in cardiovascular health by helping to regulate cholesterol levels, blood pressure, and the function of blood vessels. Women with POI are at increased risk for cardiovascular disease because of the lack of estrogen, which can lead to an increase in cholesterol levels, high blood pressure, and atherosclerosis.
• Mental health: Finally, estrogen and progesterone (which is produced largely by ovulation) play a role in mood regulation, and the lack of estrogen can increase the risk of depression in women with POI. Estrogen affects the levels of neurotransmitters such as serotonin, dopamine, and norepinephrine, which are involved in regulating mood, and having low levels of progesterone can lead to anxiety and trouble sleeping.

It's important for people with POI to work with their healthcare provider to manage their overall health and minimize any potential long-term complications. Fortunately, there are treatments available that can help minimize risk of these complications. 

POI treatments

While there is no cure for POI, hormone replacement therapy (HRT) can help alleviate some of the symptoms and improve quality of life. 

The treatment for POI aims to manage the symptoms, reduce the risk of complications, and improve the quality of life of the patient. The following are some common treatments for POI:

1. Hormone therapy: Hormone therapy can help manage the symptoms of POI, such as hot flashes, night sweats, vaginal dryness, and mood swings. Hormone therapy involves taking estrogen and progesterone in the form of pills, patches, gels, or creams.
2. Calcium and vitamin D supplements: People with POI are at a higher risk of developing osteoporosis, so calcium and vitamin D supplements may be prescribed to help maintain bone health in addition to dietary sources like full-fat dairy products and leafy greens.
3. Counseling and support: Dealing with POI can be emotionally challenging. Counseling and support groups can provide emotional support and help women cope with the emotional aspects of POI.
4. Fertility treatment: As discussed, people with POI who wish to conceive may opt for fertility treatment such as in vitro fertilization (IVF) with donor eggs.
5. Regular exercise: Regular weight-bearing exercise and strength training can help maintain bone density and prevent osteoporosis. Exercise can also improve cardiovascular health and help manage symptoms of depression.
6. Stress management: Chronic stress can contribute to symptoms of depression and anxiety, which are common in women with POI. Stress reduction techniques such as mindfulness meditation, yoga, and deep breathing exercises may help manage these symptoms.
7. Smoking cessation: Smoking is a risk factor for osteoporosis, cardiovascular disease, and certain cancers. Quitting smoking can improve overall health and reduce the risk of these conditions.
8. Acupuncture: Acupuncture has been studied as a potential treatment for POI, but the evidence is limited and conflicting. Some studies have suggested that acupuncture may improve symptoms and increase pregnancy rates in women with POI, while others have found no significant effects.

The treatment plan for POI may vary depending on the progression of the condition and the individual needs of the patient. It is important to consult with a healthcare provider to determine the appropriate treatment plan.

Conclusion

There are many unknowns about primary ovarian insufficiency, and more funding and research is needed to improve this patient experience. While it may be an alarming diagnosis to receive, it is important to remember that there are many effective management strategies that can help you live a long and normal life. 

We know this information can be overwhelming. Pollie and our dietitians, health coaches, and care coordinators are here for you every step of the way. Feel free to send an email to hello@pollie.co if you would like to learn more about how we can help you in your POI journey or download our app for free today. 

Sources

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