What is Primary Ovarian Insufficiency?
Primary Ovarian Insufficiency (POI) is a condition that affects women’s fertility and overall health, particularly due to the long-term decrease in estrogen, a vital female hormone. This condition was once known as premature ovarian failure, but that term is no longer preferred since its severity can change over time.
POI usually develops in women under the age of 40 and is identified when a woman experiences lack of menstruation for 4 to 6 months along with changes in certain hormone levels. Specifically, levels of a hormone called follicle-stimulating hormone (FSH) becomes high and the estrogen level becomes low. These hormone levels are checked twice, one month apart.
POI is different from menopause, which is the natural ending of menstruation and fertility that happens as women age. Unlike menopause, POI can fluctuate and women may still have some degree of ovarian function and eggs left. Other conditions that could stop menstruation include pregnancy, low thyroid hormone, and certain genetic abnormalities; these must be ruled out before diagnosing POI.
All women have the greatest number of eggs, around 6-7 million, while they are still in their mother’s womb around 20 weeks of pregnancy. This number drops dramatically to around 300,000-400,000 at the age a female typically starts menstruating. Once menstruation begins, the number of eggs continue to decrease over time until menopause is reached. Throughout a woman’s lifetime, only around 400-500 eggs are released during ovulation.
Normal menstruation and ovulation are important for a woman’s health. When egg release and regular menstruation aren’t happening due to conditions like POI, the body produces less sex hormones, leading to lower bone density and the development of osteoporosis or osteopenia, which increases the risk of fractures.
Therefore, it’s crucial to identify POI early in its development to prevent associated health risks and improve the quality of life for the women affected.
What Causes Primary Ovarian Insufficiency?
Primary ovarian insufficiency, or POI, is a condition where the ovaries aren’t functioning as they should or have run out of eggs. Despite ongoing research, the clear reasons behind why or how POI develops are still not completely understood. Interestingly, in about 90% of spontaneous POI cases, we can’t point out the exact cause.
One way POI can occur is if there are rare mutations in genes that regulate how the ovaries react to hormones such as FSH and LH, which are essential for the ovary to function.
Another source of POI can be due to medical treatments or certain infections that disrupt the healthy tissue in the ovaries. So, things like the surgical removal of ovaries (oophorectomy), chemotherapy, radiation or infections like mumps, chickenpox, malaria, shigella, and TB can significantly reduce the amount of functioning tissue in the ovaries.
Chromosomal abnormalities such as Turner Syndrome (where a woman only has one X chromosome instead of two) can lead to an early loss of eggs while still in the womb, or a fast decline in the number of eggs very early in life (before 10 years old). This can result in a very small or even no supply of eggs when a woman reaches reproductive age.
Changes in the FMR1 gene, specifically a variant known as Fragile X FMR1 premutation, can significantly increase a woman’s risk of POI compared to the general population.
Autoimmune diseases, where the body mistakes its own tissues for foreign invaders and starts attacking them, can be associated with POI. These can include conditions such as Addison’s disease, Hashimoto’s thyroiditis, type 1 diabetes, and rheumatoid arthritis, among others.
Certain genetic mutations and inherited diseases like galactosemia (which affects how the body processes a simple sugar called galactose), ataxia-telangiectasia (which causes problems with balance and coordination), and blepharophimosis-ptosis-epicanthus-inversus syndrome (known as BPES, a condition that affects the eyelids and ovaries) may have unknown impacts on POI.
Exposure to certain environmental factors like cigarette smoke, nicotine, and some chemicals produced by these substances are believed potentially to contribute to POI by interacting with the ovaries. Other substances like those found in plastic manufacturing may also play a part, but the exact mechanism is still not clear.
Risk Factors and Frequency for Primary Ovarian Insufficiency
Primary Ovarian Insufficiency (POI), a condition affecting women’s reproductive health, doesn’t get nearly as much attention as its impact would warrant. Roughly 1 to 2% of women under 40, and 0.1% of women under 30 suffer from POI. These figures are significantly lower than those for menopause, which generally occurs around age 50. Only about 4% of women below the age of 45 experience early menopause. What makes POI challenging is its unpredictable nature. Despite this, approximately 4-10% of women with POI can conceive naturally, yet the overall rate of successful pregnancies and live births is only about 25% after processes such as embryo freezing and implantation.
- About 20% of women with POI have successful ovulation induction.
- Around 40% chance of pregnancy is seen with donor-egg IVF after a single cycle, which goes up to 70-80% after four cycles of IVF.
- People from families affected by Fragile X Syndrome see a 13-15% prevalence of POI related to the FMR1 gene variation. In women with no family history of Fragile X Syndrome, this number is between 2-5%.
- FMR1 gene variation is associated with a 24% chance of developing POI.
- 14-27% of POI cases involve autoimmune mechanisms, specifically thyroid autoimmunity, without any adrenal pathology. 2% of cases can be traced back to insulin-dependent diabetes mellitus, and another 2% to myasthenia gravis (an autoimmune condition).
- 20% of POI patients with adrenal autoimmunity also have associated inflammation of the ovaries.
- 10-20% of women diagnosed with Addison’s disease will also be diagnosed with POI.
- Women with POI have a 4% likelihood of having 21-hydroxylase antibodies.
- Among survivors of childhood cancers who’ve undergone chemotherapy or radiation, about 8% will develop POI by 18 years of age.
- If a treatment regimen involves radiation and alkylating agents, the POI risk rises to 30%.
- For women aged 21 or older who’ve been treated with alkylating agents, 50% will develop POI.
Signs and Symptoms of Primary Ovarian Insufficiency
Checking for Primary Ovarian Insufficiency (POI) in a patient needs a full and detailed history. This involves understanding the patient’s current illness and other details that can help identify the source of the reported problem. Doctors will ask the patient’s age, any medical problems they have, their gynecological and obstetric histories, and any recent stressors.
It’s also important to know about any past illnesses, especially those that can harm the ovaries or egg supply, like mumps, shigella, tuberculosis, malaria, and varicella. Doctors will also inquire about any causes of POI due to treatments or procedures such as ovary removal, chemotherapy, or radiation.
The gynecologic history involves onset age of puberty, menstrual cycle behavior, contraceptive usage, history of sexually transmitted diseases, and any irregular Papanicolaou(smear) tests. Information about menstrual cycle such as cycle duration, amount of flow (light, moderate, or heavy), and any changes reported by the patient should be recorded. An obstetric history includes total number of pregnancies, which can then be broken down into:
- Term deliverie
- Preterm deliveries
- Abortions (voluntary or spontaneous)
- Total living children
This obstetric history also includes natural versus medically assisted conception and method of delivery, history of excessive bleeding, and any obstetric complications like gestational hypertension, diabetes, preeclampsia, eclampsia, shoulder dystocia.
Additionally, a family history of intellectual disability, shaking or unsteady movements, cognitive diseases, birth defects, or autoimmune disorders is crucial. Similarly, the social history of the patient needs to cover marital status, alcohol use, tobacco use, recreational drug use, and exercise frequency/intensity.
Finally, a thorough review of the patient’s system should be performed to aid in a more focused diagnosis based on the patient’s signs and symptoms. For example, if the patient is experiencing amenorrhea (missed periods), doctors should ask about headaches, galactorrhea (milk production when not pregnant or breastfeeding), or any vision changes as these symptoms could suggest a prolactinoma (a noncancerous tumor of the pituitary gland).
The check-up should also cover endocrine abnormalities such as intolerance to heat or cold, fatigue, weight changes, hot flashes, night sweats, increased heartbeat, excessive urination, excessive thirst, bowel movement changes, discomfort during urination, vaginal discharge, itching or dryness, or painful sexual intercourse, and neurological symptoms like intellectual disability, visual field deficits, headaches, memory issues.
The physical exam will assess vital signs such as blood pressure, heart rate, respiratory rate, and weight/body mass index. It will also include a general overview of the patient to identify any visible disease signs, such as hirsutism, obesity, and acne, which could indicate Polycystic Ovary Syndrome (PCOS), or short stature, increased carrying angle, broad chest, and neck webbing, which could indicate Turner Syndrome. The physical examination will also involve palpating the thyroid gland, which could indicate thyroid disease, and conducting a pelvic examination to identify any visible abnormalities in the genitourinary system.
Testing for Primary Ovarian Insufficiency
Primary Ovarian Insufficiency (POI), also known as premature ovarian failure, is a condition where a woman’s ovaries stop working normally before she is 40. There isn’t a universal set of criteria to diagnose POI, but if a woman stops having her monthly period (a condition known as amenorrhea), doctors typically suspect this condition.
In simpler terms, POI can be linked to a variety of health issues that may cause a female to stop having her period.
If a young woman has never had her period (primary amenorrhea), doctors start their investigation by running genetic tests to check for abnormalities such as Turner syndrome. Healthcare providers may also use a vaginal ultrasound to check for any physical irregularities in the reproductive system such as missing parts (e.g., uterus, fallopian tubes, or ovaries). One particular condition they may be checking for is Müllerian agenesis which is a rare disorder that affects the reproductive system. The ultrasound can provide information concerning the size of the ovaries and the number of potential eggs within each ovary, known as antral follicles. If a woman is diagnosed with POI, her ovaries are expected to be small with very few, if any, antral follicles present.
If a woman has stopped having her period after it began (secondary amenorrhea), doctors first perform a pregnancy test. If pregnancy is ruled out, the doctor will consider any chronic health conditions like diabetes or heart disease that could be causing the amenorrhea. The doctor may also evaluate if she’s experiencing high levels of physical activity, depression, or an eating disorder known as anorexia nervosa as these could negatively impact her reproductive health.
Various blood tests, including those that measure hormone levels like Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH), Thyroid-Stimulating Hormone (TSH), and prolactin will be conducted to identify any hormonal issues. If a woman hasn’t been menstruating for four to six months and she has high levels of FSH (indicating menopause) in two separate tests within that period, doctors may diagnose her with POI if all other test results are normal. The Antimullerian Hormone (AMH) blood test can also determine the quantity of remaining eggs in the ovaries, but it isn’t used to diagnose POI. Typically, women diagnosed with POI have AMH levels less than 1.
During the physical exam, if the doctor observes symptoms of high levels of male hormones (such as excessive hair growth, acne, enlarged clitoris or male-pattern hair loss), more tests will be done to measure levels of 17-hydroxyprogesterone, testosterone, and DHEA-S, a hormone produced by the adrenal glands. These tests will help in ruling out other conditions that might cause secondary amenorrhea, like thyroid issues (hypo- or hyperthyroidism), a prolactin-secreting tumor (prolactinoma), polycystic ovary syndrome (PCOS), or a form of adrenal gland disorder known as nonclassical congenital adrenal hyperplasia. Additionally, autoimmune disorders such as lupus, rheumatoid arthritis, myasthenia gravis, Hashimoto thyroiditis, and diabetes may also be considered.
If none of these tests can explain the cause of POI, the next step could be genetic testing, which can often be guided by the patient’s family history. However, it’s worth noting that the effect of these gene mutations on POI isn’t yet fully understood.
Treatment Options for Primary Ovarian Insufficiency
The treatment of Primary Ovarian Insufficiency (POI), also known as premature menopause, usually involves replacing the hormones that are in low supply. This is done to reduce symptoms like hot flashes, maintain bone health, reduce the risk of heart disease and certain autoimmune conditions, support brain function, and improve general wellbeing.
The goal of treatment is to ensure estrogen levels are similar to those of a woman with normal ovarian function. Common methods for replenishing estrogen include using vaginal application or transdermal patches which release estrogen into the bloodstream. These methods seem to reduce the risk of blood clots forming in the veins compared to oral estrogen replacement. This treatment should be continued until when natural menopause would typically occur (around the age of 50.5 years in the US).
For women with POI who have not had a hysterectomy, it’s also vital to include progesterone supplementation. This helps prevent the development of an overly thick uterus lining (endometrial hyperplasia), which could progress to cancer of the uterus (endometrial carcinoma). Progesterone can be given orally or through a skin patch.
For those women with POI and wishing to conceive, it can be beneficial to maintain regular menstrual cycles to optimize their chances of getting pregnant. Some women may start taking oral contraceptive pills, although these carry a higher risk of blood clots and may not keep estrogen levels as balanced as they would need to be. Women who have already gone through hysterectomy can be treated with estrogen therapy alone.
It may also offer relief from dryness, discomfort, itching, or irritation in the vagina to use topical estrogen creams. The best way for women with POI to achieve pregnancy is not through stimulating the ovaries to release eggs (ovulation induction) but through the use of donated eggs (oocyte donation).
Being diagnosed with POI can be distressing for women but also their partners and families. Regular medical follow-up and providing the necessary support to see mental health professionals can help manage the emotional stress related to this condition.
What else can Primary Ovarian Insufficiency be?
When diagnosing Periodic Ovarian Insufficiency (POI), doctors need to consider several other health conditions that may present with similar symptoms. These conditions are not always accompanied by POI. The list of considerations is different for patients displaying primary and secondary amenorrhea (the absence of menstrual periods).
In patients who have primary amenorrhea, the doctor needs to rule out possible genetic abnormalities such as Turner syndrome, or abnormalities in the reproductive tract like Mullerian anomalies. These include conditions like Mullerian agenesis or an imperforate hymen.
For women with secondary amenorrhea, the first thing to consider is whether pregnancy could be the cause. Doctors also need to assess the patient’s nutrition and activity level, to see if hormonal imbalances from the hypothalamus are causing the irregular periods. Other hormonal conditions such as irregular thyroid function, prolactinoma, diabetes, and congenital adrenal hyperplasia can also cause infertility, without the presence of POI.
Some autoimmune disorders like systemic lupus erythematosus, rheumatoid arthritis, or Addison’s disease can occur even without evidence of POI. Polycystic ovarian syndrome could be the reason behind the irregular periods and lack of ovulation leading to infertility. Finally, for women in their 40s but under 45, early menopause may also need to be considered.
What to expect with Primary Ovarian Insufficiency
Primary ovarian insufficiency (POI), a condition that affects a woman’s fertility, should be diagnosed only after ruling out other possible medical conditions. It’s essential to remember that this diagnosis carries heavy implications for a woman’s future health, her ability to have children, and her mental well-being.
At the moment, sadly, there are no treatments that can repair the damage to healthy eggs, improve the functionality of existing eggs, or create new eggs. That said, there’s still a small chance for a woman with POI to get pregnant naturally, as the course of this condition can be unpredictable.
If a woman with POI wants to have a child, the most successful treatment at the moment is egg donation.
Possible Complications When Diagnosed with Primary Ovarian Insufficiency
POI, or primary ovarian insufficiency, can have a range of symptoms that make life difficult for women. These can include hot flashes, mood swings, night sweats, trouble sleeping, vaginal dryness and discomfort during sex. While these symptoms are not life-threatening, they can be eased with hormone replacement therapy.
However, hormone replacement therapy can lead to potentially serious complications. These complications can be very serious, including increased risk of deep vein thrombosis (blood clot), pulmonary embolism (a blockage in the lungs), and stroke.
Over the long-term, POI can lead to other problems. These can include decreased mental function and lower bone mineral density. The lower density can lead to conditions like osteoporosis and osteopenia, which increase the risk of fractures. The biggest effect of POI is on a woman’s cardiovascular health, leading to the potential for premature death from heart diseases.
It should also be noted that the inability to have children resulting from POI can cause lasting mental and emotional effects. This can include anxiety, depression, and sexual disorders, all of which can negatively affect a woman’s quality of life.
Referenced Complications:
- Hot flashes
- Mood swings
- Night sweats
- Trouble sleeping
- Vaginal dryness
- Discomfort during sex
- Potentially lethal blood clot
- Blockage in the lungs
- Stroke
- Decreased mental function
- Lower bone mineral density
- Osteoporosis and osteopenia
- Increased risk of fractures
- Premature death from heart diseases
- Anxiety, depression, and sexual disorders
Preventing Primary Ovarian Insufficiency
Finding out you have primary ovarian insufficiency (POI), a condition where the ovaries stop working normally before age 40, can be really tough, especially for women who want to have children. While POI isn’t life-threatening, it can affect a woman’s overall health and wellbeing. Doctors should be straightforward with their patients about this diagnosis, but also reassure them that many of the physical symptoms of POI, like irregular periods, can be managed with hormone replacement therapy.
Another reassuring thing is that spontaneous pregnancy can still occur, because the progression of POI doesn’t follow a set path and can be unpredictable. It’s also crucial for doctors to provide support and point patients towards resources that can help them deal with the emotional stress (such as anxiety, depression, guilt, decreased sexual desire) that can come along with POI.
Part of this support is having open and informative conversations with patients regarding how low estrogen levels, a symptom of POI, can affect their bones, hearts, brains, and mental health. People with POI will need regular check-ins with their doctor to make sure they’re getting the hormone replacement they need and aren’t having any negative side effects from the medication.
But with the right hormone treatment, women with POI can lead healthy and fulfilling lives.
