Primary ovarian insufficiency (premature ovarian failure) is a condition where your periods stop suddenly and spontaneously, either early or prematurely. Primary ovarian insufficiency (premature ovarian failure) isn’t the same as premature or early menopause, because with primary ovarian insufficiency, there’s a chance your period will come back. People with primary ovarian insufficiency may still ovulate, menstruate or become pregnant. With early or premature menopause, you don’t ovulate or menstruate, and you lose the ability to get pregnant.

How do I know if I am going through early or premature menopause?

You know you have gone through menopause when you have not had your period for 12 months in a row. If you think you may be reaching menopause early, talk to your doctor.

• Your doctor will ask you about your symptoms, such as hot flashes, irregular periods, sleep problems, and vaginal dryness.
• Your doctor may give you a blood test to measure estrogen and related hormones, like follicle-stimulating hormone (FSH). You may choose to get tested if you want to know whether you can still get pregnant. Your doctor will test your hormone levels in the first few days of your menstrual cycle (when bleeding begins).

Can you reverse premature menopause?

You can’t reverse menopause or make your ovaries function normally again. However, your doctor can help reduce the symptoms and side effects of menopause. In the case of primary ovarian insufficiency (POI), there’s a small possibility you’ll regain ovarian function.

How can I reduce my risk of premature menopause?

Most causes of premature menopause are beyond your control (see Premature menopause causes). Smoking cigarettes is the only lifestyle factor that may cause early menopause. You can reduce your risk of menopause by quitting smoking. The other causes of menopause like health conditions, surgeries or treatment for cancer are unpreventable in most cases.

If I have premature menopause, can I still have children?

Women with primary ovarian insufficiency (premature ovarian failure) do sometimes ovulate, and pregnancy can occur naturally, which is why contraception is still recommended for those who do not desire pregnancy. However, the chance of a natural pregnancy is low, occurring in less than 10% of women with primary ovarian insufficiency (premature ovarian failure). For women with primary ovarian insufficiency (premature ovarian failure) who desire children, there is increasing information and testing available about the number of remaining healthy eggs a woman has (her ovarian reserve) and how this relates to her chance of getting pregnant. A referral to a fertility specialist or a reproductive endocrinologist may be beneficial.

It’s possible to get pregnant through in vitro fertilization (IVF) after menopause. You can use eggs from a donor or your own eggs (if you froze your eggs prior to menopause). Any eggs that are left after menopause typically aren’t viable. Surrogacy and adoption are also options.

Can my menstrual periods return if they’ve stopped after having chemotherapy or radiation therapy?

It is possible that your periods may return after your ovaries have had time to recover after one of these therapies. However, the more time that passes without having a period, the less likely you are to have one again.

How do you know if you are starting premature menopause?

You may start having irregular menstrual cycles for a few years prior to your last menstrual period. Longer or shorter menstrual cycles, spotting between periods or changes in vaginal bleeding are often some of the first signs of menopause. If you experience irregular periods, speak with a doctor to look into possible causes.

The other signs of premature and early menopause include many of the typical menopause symptoms. You may experience:

• Hot flashes (sudden warmth that spreads over your body).
• Night sweats.
• Vaginal dryness and discomfort during sex.
• Frequent urge to pee.
• More frequent urinary tract infections (UTIs).
• Difficulty sleeping (insomnia).
• Emotional changes (irritability, mood swings, depression or anxiety).
• Dry skin, dry eyes or dry mouth.
• Breast tenderness.
• Racing heart.
• Headaches.
• Joint and muscle aches and pains.
• Changes in your sex drive (libido).
• Difficulty concentrating or being more forgetful.
• Weight gain or weight loss.
• Hair loss or thinning.

Premature menopause causes

Many of the causes of premature menopause can also be causes of early menopause. Some causes of premature menopause include cancer treatment, surgery or certain health conditions. But, sometimes, the cause is unknown. Anything that damages your ovaries or stops your body from making estrogen can cause menopause.

There are two types of premature menopause, primary and secondary. Primary premature menopause means that your ovaries do not function normally. This may be because they have been removed by surgery, or it may be caused by some cancer treatments and certain diseases or genetic conditions. In secondary premature menopause, the ovaries are normal but there is a problem getting hormone signals to them from your brain. This is usually caused by diseases of the pituitary gland or hypothalamus. Some women with premature menopause sometimes have menstrual periods and may be able to have children.

Reasons for premature menopause can include:

• Family history. Women with a family history of early or premature menopause are more likely to have early or premature menopause.
• Smoking. Women who smoke may reach menopause as much as two years before nonsmokers. They may also get more severe menopause symptoms ³⁹. Research suggests that women who have early or premature menopause and smoke die about two years earlier than nonsmoking women ⁴⁰.
• Chemotherapy or pelvic radiation treatments for cancer. These treatments can damage your ovaries and cause your periods to stop forever or just for a while. You also may have trouble getting pregnant or not be able to get pregnant again. However, not all women who have chemotherapy or radiation will go through menopause. The younger a woman is at the time of chemotherapy or radiation, the less likely she is to go through menopause.
• Surgery to remove the ovaries. Surgical removal of both ovaries, called a bilateral oophorectomy, may cause menopausal symptoms right away. Your periods will stop after this surgery, and your hormone levels will drop quickly. You may have strong menopausal symptoms, like hot flashes and less sexual desire.
• Surgery to remove the uterus. Some women who have a hysterectomy, which removes the uterus, can keep their ovaries. If this happens, you will no longer have periods, and you cannot get pregnant. But you will probably not go through menopause right away because your ovaries will continue to make hormones. Later on, you might have natural menopause a year or two earlier than expected.
• Certain health conditions:
  • Autoimmune diseases. Autoimmune disorder such as thyroiditis, vitiligo, myasthenia gravis, Addison disease (adrenal insufficiency) and rheumatoid arthritis. Although rare, the body’s immune system, which normally fights off diseases, may mistakenly attack the ovaries and keep them from making hormones.
  • HIV and AIDS. Women with HIV whose infection is not well controlled with medicine may experience early menopause ²⁹. Women with HIV may also have more severe hot flashes than women without HIV ³⁰.
  • Missing chromosomes. Women born with missing chromosomes or problems with chromosomes can go through menopause early. For example, women with the condition called Turner’s syndrome are born without all or part of one X chromosome, so their ovaries do not form normally at birth and their menstrual cycles, including the time around menopause, may not be normal.
  • Chronic fatigue syndrome. Women with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) have extreme tiredness, weakness, muscle and joint pain, memory loss, headache, unrefreshing sleep, and other symptoms. Research has found that women with myalgic encephalomyelitis / chronic fatigue syndrome are more likely to have early or premature menopause ⁴¹.

Induced premature menopause

Induced menopause occurs when a medical treatment, such as surgery, chemotherapy, or radiation, removes or seriously damages both ovaries. The reason for the medical treatment may affect whether hormone therapy will be recommended.

• Surgery that removes both ovaries called bilateral oophorectomy: Your ovaries make hormones, including estrogen and progesterone, that control your menstrual cycle. When both ovaries are surgically removed, menopause results. Cancer is a common reason for this surgery. Removing both ovaries may be done to treat ovarian cancer or to help prevent breast and ovarian cancer in women who are considered to be at high risk. You’re likely to have hot flashes and other menopausal symptoms. Symptoms can be severe because the surgery causes hormones to drop all at once rather than slowly over several years.
• Chemotherapy: Chemotherapy is a powerful drug therapy to treat various types of cancer. Chemotherapy may be used along with surgery, radiation therapy, or both. Periods sometimes return after chemotherapy. Then you can still get pregnant. So you might want to keep using birth control.
• Radiation therapy: Radiation therapy uses high-energy particles or waves to damage cancer cells and reduce their size or keep them from growing. Radiation therapy aimed at the pelvis, belly and lower spine can cause menopause. Radiation to the whole body for stem cell transplant also can cause menopause. Radiation therapy to other parts of the body, such as breast tissue or the head and neck, likely won’t affect menopause.

Primary ovarian insufficiency

Primary ovarian insufficiency also called premature ovarian failure is a condition in which younger women skip many periods in a row or have no periods at all. In most cases, the exact cause of primary ovarian insufficiency is unknown ²⁴, ²⁵, ²⁶. Approximately 90% of all diagnosed cases of spontaneous primary ovarian insufficiency do not have a determined underlying cause ³¹. Research shows that primary ovarian insufficiency is related to problems with the ovarian follicles, the small sacs in the ovaries in which eggs grow and mature ²⁶. Ovarian 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 ²⁸, typically enough to last until she goes through natural menopause, usually around age 50 ²⁵.

For a woman with primary ovarian insufficiency there are problems with the ovarian follicles ⁴²:

• Follicle depletion. A woman with follicle depletion runs out of working follicles earlier than normal or expected. In the case of primary ovarian insufficiency, 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 ²⁶.

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

• Genetic and chromosomal disorders.
  • Starting at the level of the ovary, rare mutations in the genes for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) receptors can alter the ovaries’ response to these circulating gonadotropins leading to nonfunctional ovarian tissue ²⁷, ²⁸, ²⁶.
  • Chromosomal abnormalities such as Fragile X syndrome and Turner syndrome can cause accelerated egg (oocyte) depletion early in life ²⁶, ²⁸, ⁴³.
  • Genetic mutations and autosomal recessive diseases such as galactosemia (reduction of galactose-1-phosphate), ataxia-telangiectasia (ATM gene), and blepharophimosis-ptosis-epicanthus-inversus syndrome (known as BPES, a mutation in FOXL2) have undefined effects on primary ovarian insufficiency ²⁶, ²⁸, ⁴³.
• 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 primary ovarian insufficiency, 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 primary ovarian insufficiency have an autoimmune disease ²⁵, ⁴⁴.
  • Thyroiditis such as Hashimoto thyroiditis is the autoimmune disorder most commonly associated with primary ovarian insufficiency ⁴⁴. It is an inflammation of the thyroid gland, which makes hormones that control metabolism, or the pace of body processes.
  • Addison’s disease (adrenal insufficiency) is also associated with primary ovarian insufficiency. 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 ⁴⁵. A small percentage of women with primary ovarian insufficiency have Addison’s disease.
  • Rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes, nontypical congenital adrenal hyperplasia, myasthenia gravis, and inflammatory bowel disease (Crohn’s disease and ulcerative colitis) have also been associated with primary ovarian insufficiency ²⁶, ²⁷.
• Chemotherapy or radiation therapy. These strong treatments for cancer may damage the genetic material in cells, including follicle cells ²⁴, ²⁶.
• Metabolic disorders. Metabolic 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 primary ovarian insufficiency ⁴⁴.
• Women with mumps, chickenpox, malaria, shigella, and tuberculosis (TB) can destroy healthy ovarian tissue and substantially decrease the amount of functioning tissue that remains ²⁵, ²⁷, ²⁸, ²⁶.
• Toxins. Cigarette smoke, chemicals, nicotine, phthalates, polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substance (PFAS), bisphenol-A (BPA), dimethylbenzanthracene and pesticides can speed up ovarian follicle depletion.
• Viruses have been shown to affect follicle function ²⁸, ²⁵.

A blood test may report a high follicle-stimulating hormone (FSH) level, which can be a sign of menopause and of few eggs left in the ovaries. However, the release of an egg from an ovary (ovulation) may still occur on occasion, which means that pregnancy is still possible.

Some women with primary ovarian insufficiency experience typical menopause symptoms, whereas others do not. If they do experience symptoms, they may be intermittent. Some women resume normal periods at some point, and others do not. There are several known causes of primary ovarian insufficiency, including certain genetic and autoimmune disorders. Unfortunately, much is still unknown about this condition, which makes it difficult to predict what will happen. Women aged younger than 40 years who have missed three or more menstrual periods are advised to see a healthcare professional to determine whether this is caused by primary ovarian insufficiency or whether another reason for absent or irregular menstruation is at play.

Risk factors for premature menopause

The main risk factor for premature menopause include:

• Surgery to remove both ovaries.
• Certain cancer treatments e.g., chemotherapy, radiation therapy.
• Smoking. Women who smoked at age 16 had 51% higher odds of early menopause, compared to those who did not smoke at this age
• Genetic abnormality (e.g. Turner syndrome or Fragile X syndrome)
• Metabolic disorders
• Viral infection (e.g. mumps).
• Autoimmune diseases such as Addison’s disease, thyroid disease, type 1 diabetes, Crohns’ disease and coeliac disease

Premature menopause signs and symptoms

Women who go through menopause early may have symptoms or health problems similar to those of regular menopause. Different people have different menopause symptoms. Some women may have no symptoms, except that menstrual periods become lighter or irregular, or stop (amenorrhea). Women who haven’t had a menstrual period for 12 straight months, and aren’t on any medication that could stop menstruation, may have reached menopause. Other women have infertility or develop the same symptoms that are associated with normal menopause (which occurs at about age 51), such as hot flashes, night sweats, or mood swings.

Most people who go through menopause experience some symptoms include the following:

• Irregular periods. This is one of the first signs of nearing menopause. You may skip periods, or they may occur closer together. Your flow may be lighter or heavier than usual.
• Hot flashes. Hot flashes are the most common symptom of menopause. When you have a hot flash, you’ll feel warm from your chest to your head. These often happen in wave-like sensations. Your skin may turn red, and you may sweat. You may feel sick to your stomach and dizzy. You may also have a headache and feel like your heart is beating very fast and hard.
• Vaginal dryness. During and after menopause, the skin of your vagina and vulva (the area around your vagina) becomes thinner. Your vagina also loses its ability to produce as much lubrication (wetness) during sexual arousal. These changes can lead to pain during sex. You may need to help supplement vaginal moisture to make having sex less painful. You can use an over-the-counter water-based sexual lubricant (such as K-Y Jelly). Or you can use moisturizers for the vaginal area (such as Vagisil). You can also talk to your doctor about the benefits and risks of using prescription estrogen cream for vaginal changes. Topical estrogens are absorbed into the bloodstream and cause many of the same side effects as when they are taken by mouth. Estrogens used vaginally at very low doses will not protect against osteoporosis or stop the hot flashes caused by menopause. They can interact with other medicines and conditions.
• Urinary tract problems. You’re more likely to have bladder and urinary tract infections during and after menopause. Talk to your doctor if you have to go to the bathroom more often or feel an urgent need to urinate. Also let your doctor know if you feel a burning sensation when urinating or are not able to urinate.
• Headaches, night sweats, trouble sleeping, and tiredness. As you’re going through menopause, you may have trouble falling asleep or staying asleep. Night sweats may wake you up. You may not get enough rapid eye movement (REM) sleep (the stage of sleep during which you dream). A lack of REM sleep may make you feel tired, moody, and stressed out.
• Mood swings or be irritable. Many people experience emotional symptoms during menopause. These symptoms may include sadness, anxiety, and mood swings. For some people, symptoms can be severe. If you find that you’re having emotional problems, talk to your family doctor.
  
• Trouble finding words and remembering, often called brain fog.
• Weight gain. Many people gain weight (an average of 5 pounds) during menopause. A healthy diet and exercising most, if not all, days of the week will help keep you fit.

Women may have symptoms of the disorder that caused premature menopause. For example, if Turner syndrome is the cause, they may have physical or cognitive abnormalities.

If premature menopause is caused by an autoimmune process, women may also have other autoimmune disorders such as thyroiditis, vitiligo, myasthenia gravis, and Addison disease (adrenal insufficiency). Addison disease can be life threatening (Addisonian crisis).

The lack of estrogen may lead to thinning and drying of the lining of the vagina (vaginal atrophy). The risk of other conditions such as depression, anxiety, Parkinson disease, dementia, and coronary artery disease, may be increased.

Some women with premature menopause may also have:

• Higher risk of serious health problems. For example, you might begin to lose bone density because you have less estrogen. This can lead to osteoporosis, a condition that causes bones to become weak and break easily. Changing estrogen levels can also raise your cholesterol levels and increase your risk for heart disease and stroke. Talk to your doctor about steps to lower your risk for these health problems.
• More severe menopause symptoms. Talk to your doctor about treatments to help with symptoms if they affect your daily life.
• Sadness or depression over the early loss of fertility or the change in their bodies. Talk to your doctor if you have symptoms of depression, including less energy or a lack of interest in things you once enjoyed that lasts longer than a few weeks. Your doctor can recommend specialists who can help you deal with your feelings. Your doctor can also discuss options, such as adoption or donor egg programs, if you want to have children.

Premature menopause complications

Unless women with premature menopause receive estrogen therapy until about age 51 (the average age for menopause), the risk of osteoporosis, dementia, Parkinson disease, depression, and coronary artery disease is increased.

• Heart and blood vessel disease. This also is called cardiovascular disease. When your estrogen levels fall, your risk of cardiovascular disease increases. Heart disease is the leading cause of death in both women and men.
• Weakened bones called osteoporosis. This condition causes bones to become brittle and weak, leading to a greater risk of breaking bones. During the first few years after menopause, you may lose bone density quickly. This ups your risk of osteoporosis. Bones often broken after menopause include the spine, hips and wrists.
• Loss of bladder control called urinary incontinence. As the tissues of your vagina and urethra change, you may have sudden, strong urges to urinate often. Then you might lose urine, called urge incontinence. Or you might lose urine with coughing, laughing or lifting, called stress incontinence. You may have urinary tract infections more often.
• Sex problems. Menopause causes the vagina to get drier and lose its stretch. This can cause discomfort and slight bleeding during sexual intercourse. Also, less feeling in the area may lessen your desire for sex, called libido.
• Weight gain. Many women gain weight during and after menopause because calorie burning, called metabolism, slows.

If premature menopause is caused by an autoimmune disorder, women are at risk of potentially life-threatening primary adrenal insufficiency (Addison disease).

Bone loss and fracture

Women with primary ovarian insufficiency-related estrogen deficiency are at risk of osteopenia, osteoporosis, and fracture, especially if estrogen deficiency (hypoestrogenism) occurs early in life and before accrual of peak bone mass ⁴⁶, ⁴⁷, ¹², ⁴⁸. A number of large, well-designed prospective studies have provided strong evidence that early age at menopause, especially when occurring at 45 years or younger, is associated with a risk of fracture that is 1.5 to 3 fold higher than the risk for women who experience menopause after age 50 years ¹², ⁴⁹, ⁵⁰, ⁵¹, ⁵². In a study of more than 1,000 patients, the incidence of hip fracture in women starting menopause at age 40 years was 9.4% compared with 3.3% in those starting menopause at age 48 years ⁴⁹. In the Rotterdam study, a prospective population-based cohort study that evaluated risk factors for incident fractures among 3,000 men and women, vertebral fracture was 2.5 times more likely to occur in women who experienced menopause before age 45 years compared with those who experienced menopause after age 50 years ⁵². In studies that have evaluated the role of hormone replacement therapy (HRT) in women at increased risk of fracture based on menopausal age, significant reductions in fracture risk have been described ¹², ⁵¹, ⁵².

Other risk factors for low bone mass in women with primary ovarian insufficiency include delay in primary ovarian insufficiency diagnosis of 1 year or more, vitamin D deficiency, nonadherence to prescribed hormone replacement therapy (HRT), sedentary lifestyle, and lack of calcium supplementation ⁴⁸. Dual-energy X-ray absorptiometry (DEXA scan) has been recommended for the evaluation of bone mineral density in women diagnosed with primary ovarian insufficiency, but consensus regarding the frequency of interval surveillance is lacking, especially in adolescent girls ²⁵, ⁴⁶, ⁵³. In contrast to the treatment of postmenopausal osteopenia or osteoporosis, which focuses on bisphosphonates as first-line therapy, low bone mass in women with primary ovarian insufficiency is managed most appropriately with hormone replacement therapy (HRT) ⁵⁴. Given the extremely long half-life of bisphosphonates, there is concern regarding the safety of this class of drugs in young women with primary ovarian insufficiency, who could spontaneously become pregnant or pursue donor egg in vitro fertilization (IVF) to achieve a pregnancy ⁵⁵. To date, long-term use of bisphosphonates is not recommended in the adolescent girl population because of uncertain adverse effects and safety profiles ⁴⁶.

Cardiovascular disease

Postmenopausal women have less favorable lipid profiles compared with premenopausal women and the risk of metabolic syndrome has been shown to increase after menopausal transition ⁵⁶, ⁵⁷. Women who develop primary ovarian insufficiency are also at increased risk of cardiovascular events and cardiovascular mortality compared with women who do not experience early menopause ⁵⁸, ⁵⁹, ⁶⁰. In a 20-year follow-up of a 12,000-woman cohort study conducted in the Netherlands, cardiovascular mortality decreased by 2% for every year that menopause was delayed after age 39 years ⁶⁰. In a subsequent prospective cohort study that monitored more than 6,000 U.S. women for 12 years, patients who reported experiencing menopause between the ages of 35 years and 40 years at study entry had a 50% greater subsequent risk of ischemic heart disease-related death (risk adjusted for diabetes, hypertension, parity, age at first birth, and physical activity) compared with those who experienced menopause between the ages of 49 years and 51 years ⁵⁸. The association between primary ovarian insufficiency and cardiovascular disease risk may be explained in part by metabolic and endothelial changes that occur with estrogen deprivation. A cohort study observed significant endothelial dysfunction in women with primary ovarian insufficiency compared with age- and body mass index-matched women, demonstrated by diminished flow-mediated brachial artery diameter. After 6 months of hormone replacement therapy (HRT), the brachial artery diameters of women with primary ovarian insufficiency were comparable with those of the control group ⁶¹. In this study and others, hormone replacement therapy (HRT) has been shown to improve endothelial dysfunction and reduce intima media thickness ⁶², blood pressure, plasma angiotensin, and creatinine ⁶³. Primary ovarian insufficiency also may be related to cardiovascular disease risk and death as an indicator of overall aging and age-related illness ⁶⁴, ⁶⁵.

Epidemiologic evidence supporting the use of hormone replacement therapy (HRT) to prevent cardiovascular events in women with primary ovarian insufficiency is currently lacking. However, there also are no data that indicate that women with primary ovarian insufficiency who are treated with hormone replacement therapy (HRT) experience an increased risk of cardiovascular adverse effects compared with unaffected women using hormone replacement therapy (HRT) or combination hormonal contraceptives (daily combined estrogen–progestin in the form of combination oral birth control pills, the contraceptive ring, or transdermal patches) ⁴⁶, ⁴⁴.

Vasomotor symptoms

Women with primary ovarian insufficiency may experience hot flushes, night sweats, vaginal dryness, dyspareunia, and disordered sleep; some symptoms may develop before cycle irregularity ²⁵. These symptoms routinely respond well to hormone replacement therapy (HRT) as indicated. Some women may be asymptomatic; younger women in particular may not exhibit symptoms.

Cognition, Mood, and Psychosocial symptoms

Evidence regarding cognitive decline in women with primary ovarian insufficiency is limited and mixed. A cohort study reported that young (defined as younger than 43 years) surgically menopausal women who were not receiving hormone replacement therapy (HRT) demonstrated signs of cognitive impairment compared with controls ⁶⁶. These findings contrast with other reports that suggest preserved cognitive function in women with primary ovarian insufficiency who have intact ovaries ⁶⁷.

Primary ovarian insufficiency has been referred to as “the silent grief” because of the negative self-image and isolation that can develop once a diagnosis is confirmed ⁶⁸. Women with primary ovarian insufficiency who were surveyed about their diagnosis report significant levels of grief, diminished self-esteem, sadness, and limited access to psychological support to address these feelings ⁶⁸, ⁴⁶, ⁶⁹, ⁷⁰, ⁷¹, ⁷². Poor psychosocial functioning is explained, in small part, by vasomotor symptoms in this population ⁷³. The emotional response to a diagnosis of primary ovarian insufficiency may be more complex and challenging in the adolescent population than for adults. Support from family or mental health professionals is important to facilitate the understanding and acceptance of the diagnosis ⁷³, ²⁵, ⁴⁶.

Emotional wellbeing

Women who experience premature menopause can be at greater risk of depression, anxiety and mood changes. If you experience menopause in your 20s or 30s, it can be very upsetting. It’s normal to feel a sense of loss, sadness and grief. You may also have mixed feelings about your body image, fertility, femininity and sexuality.

There are lots of things you can do to look after yourself during this difficult time. If you feel very emotional, anxious or depressed after your diagnosis, it’s important to talk to someone. You can do counselling or join a support group. Your doctor can help with symptom relief and refer you to a psychologist if needed.

Sex and relationships

After a diagnosis of premature menopause, physical and emotional changes may reduce your desire to be intimate with your partner. It can be distressing to have hot flushes and sweats at a young age. You might also feel conscious of physical changes, like vaginal dryness, which can cause pain during sex and result in a reduced sex drive (libido).

Depending on your stage of life and family plans, this diagnosis may change your plans and affect your relationship.

It’s important to seek support from people close to you. If you have a partner, they might not know about menopause symptoms or what you are going through. You can suggest going to your gynaecologist or doctor’s appointments together or seek counselling if required.

Premature menopause diagnosis

If you believe you are going through premature menopause and have concerns, see your doctor. Doctors suspect premature menopause when a woman younger than 40 of years of age has menopausal symptoms, or few or no periods, or cannot become pregnant (infertile). Your doctor may order a blood test to check your hormone levels.

If a woman is younger than age 40 and begins having irregular periods or stops having periods for 4 months or longer, her doctor may take these steps to diagnose the problem ⁷⁴, ⁷⁵, ⁷⁶:

• Do a physical exam. During the physical exam, your doctor looks for signs of other disorders. In some cases, the presence of these other disorders will rule out primary ovarian insufficiency. Or, if the other disorders are associated with primary ovarian insufficiency, such as Addison’s disease. If on the physical exam there is evidence of high levels of androgens (male sex hormones e.g., testosterone, androsterone and androstenedione in women), such as hirsutism, acne, enlarged clitoris (clitoromegaly), or male pattern baldness, then it would be appropriate to evaluate the levels of 17-hydroxyprogesterone (21-hydroxylase antibodies), testosterone, and DHEA-S ⁷⁷. The aforementioned laboratory work would help to include or exclude the diagnosis of thyroid dysfunction (hypo- or hyperthyroidism) versus prolactinoma versus polycystic ovarian syndrome (PCOS) versus nontypical congenital adrenal hyperplasia that could be the cause of the patient’s secondary amenorrhea.
• Do a pregnancy test. This test will rule out an unexpected pregnancy as the reason for missed periods.
• Measurement of hormone levels
  • Follicle-stimulating hormone (FSH) and estrogen (estradiol). Follicle-stimulating hormone (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 your ovaries are not working properly, as is the case in premature menopause, the level of follicle-stimulating hormone (FSH) in your blood increases and estrogen goes down. Your doctor 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 premature menopause is likely.
  • Luteinizing hormone (LH). Luteinizing hormone (LH) signals a mature follicle to release an egg. Women with primary ovarian insufficiency have high luteinizing hormone (LH) levels, more evidence that the follicles are not functioning normally ⁴².
  • Thyroid-stimulating hormone (TSH). Overactive thyroid, called hyperthyroidism, can cause symptoms like those of menopause.
  • Antimullerian hormone (AMH) can be obtained and is used as a marker for ovarian reserve, but is not part of the diagnostic criteria for primary ovarian insufficiency ²⁷. A blood test for antimüllerian hormone (AMH) can be done to evaluate how well the ovaries are functioning and to estimate the chances that a woman will be able to become pregnant after treatment with fertility medications. Normal antimüllerian hormone (AMH) levels are between 1.5 and 4.0 ng/mL. Most women diagnosed with primary ovarian insufficiency have antimüllerian hormone (AMH) levels less than 1 ng/mL ⁷⁷. A very low antimüllerian hormone (AMH) level suggests decreased ovarian reserve. Reproductive endocrinologists use antimüllerian hormone (AMH) levels to help predict which women may respond poorly to fertility medications and generally which couples are less likely to be successful with fertility treatment. Antimüllerian hormone (AMH) can be drawn at any time during the menstrual cycle. Newer, more sensitive antimüllerian hormone tests may help clinicians diagnose early menopause.
• Genetic counseling and testing for the FMR1 premutation (Fragile X mutation) are indicated if women have a family history of primary ovarian insufficiency or have intellectual disability, tremor, or loss of balance (ataxia) or have a close relative with premature menopause or if they are younger than 35.
• 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 primary ovarian insufficiency and other health problems ²⁵, ⁴².
• Pelvic ultrasound. In this test, your doctor 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 ²⁴, ²⁵.

Autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis, myasthenia gravis, Hashimoto thyroiditis (thyroid peroxidase autoantibodies and antithyroglobulin antibodies), and diabetes mellitus should also be considered ²⁷. If doctors suspect a woman also has Hashimoto thyroiditis (an autoimmune disorder), they measure thyroid hormone levels in the blood such as thyroid-stimulating hormone (TSH), thyroxine (T4), and antithyroid–peroxidase and antithyroglobulin antibodies. If adrenal insufficiency is suspected, measurement of a morning cortisol level or an adrenocorticotropic hormone (ACTH) stimulation test can confirm the diagnosis.

Other tests for an autoimmune dysfunction should be done; they include a complete blood count with differential, erythrocyte sedimentation rate (ESR), and measurement of antinuclear antibody and rheumatoid factor.

Bone density may be measured to check for osteoporosis if women have symptoms or signs of estrogen deficiency.

Premature menopause treatment

If a woman with premature menopause does not wish to become pregnant, she is given one of the following:

• Birth control pills or a patch that contains estrogen and a progestin (combination oral contraceptives)
• Menopausal hormone therapy (MHT) also called hormone replacement therapy (HRT) that contains both estrogen and a progestin (a synthetic form of the female hormone progesterone) or progesterone. In women with primary ovarian insufficiency, systemic hormone replacement therapy (HRT) is an effective approach to treat the symptoms of hypoestrogenism and reduce long-term health risks if there are no contraindications to treatment. Hormone replacement therapy (HRT) is indicated to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy and to improve the quality of life of women with primary ovarian insufficiency. The results from the Women’s Health Initiative trials related to menopause therapy are not applicable to young women with primary ovarian insufficiency whose exposure to physiologic estrogen has been withdrawn prematurely. When hormone replacement therapy (HRT) is withheld from women with primary ovarian insufficiency because of extrapolation of good epidemiologic evidence from the wrong population, those women may experience many negative health consequences.

These treatments are typically taken until about age 51 (the average age for menopause). Then, doctors decide whether to continue the treatments based on a woman’s individual circumstances.

Estrogen therapy helps relieve symptoms and helps prevent other effects of menopause (such as vaginal dryness, and mood swings). It also helps maintain bone density (to prevent osteoporosis). Because taking estrogen alone increases the risk of cancer of the uterine lining (endometrial cancer), most women should also take a progestin or progesterone with the estrogen to help protect against this cancer. Women who have had a hysterectomy (removal of the uterus) do not need to take a progestin or progesterone.

If a woman with premature menopause wishes to become pregnant, doctors may recommend in vitro fertilization (IVF) using another woman’s eggs (donor eggs). These eggs are implanted in the uterus after they have been fertilized in the laboratory. This technique gives women with premature menopause about a 50% chance (sometimes even higher) of becoming pregnant. Otherwise about 5 to 10% of women with primary ovarian insufficiency eventually become pregnant on their own, without fertility treatments. No treatment has been proved to increase the ovulation rate or restore fertility in women with primary ovarian insufficiency.

Other options for women who desire pregnancy include cryopreservation of ovarian tissue, oocytes, or embryos and embryo donation. These techniques may be used before or during ovarian failure, especially in cancer patients. Neonatal and adult ovaries possess a small number of oogonial stem cells that can stably proliferate for months and produce mature oocytes in vitro; these cells may be used to develop infertility treatments in the future. Ovarian tissue transplantation has been successful and, in the future, may become an option for women who are no longer fertile ⁷⁸.

Unless contraindicated, hormonal therapy or estrogen/progestin contraceptives are recommended rather than other bone-specific treatments (eg, bisphosphonates) to prevent bone loss in women with premature ovarian insufficiency; these treatments are given until women reach the average age for menopause (about age 51), when treatment may be reassessed.

To help prevent osteoporosis, women with primary ovarian insufficiency should consume an adequate amount of calcium and vitamin D (in the diet and/or as supplements).

Women with a Y chromosome require bilateral oophorectomy via laparotomy or laparoscopy because risk of ovarian germ cell cancer is increased ⁷⁶.

Hormone replacement therapy (HRT)

Hormone replacement therapy (HRT) is the most common form of prescribed treatment for menopausal symptoms. Hormone replacement therapy (HRT) helps to replace the hormone estrogen in your body, which decreases around your menopause. You may sometimes also need other hormones such as progesterone and testosterone that your body is no longer producing. Hormone replacement therapy (HRT) may reduce associated menopause symptoms, bone mineral density loss, and cardiovascular risk and should be continued until the age of natural menopause (50 to 51 years) ³², ⁷⁹, ⁸⁰, ³³, ³⁴, ⁸¹. If you are interested in taking hormone replacement therapy (HRT), your doctor should discuss the benefits and risks with you before you start the treatment. This discussion should cover both the short-term (over the next 5 years) and the longer term (beyond the next 5 years) benefits and risks for you. You should also be informed about available alternatives to hormone replacement therapy (HRT) along with their benefits and risks.

Unopposed estrogen replacement therapy is an important risk factor for endometrial hyperplasia (10–50% incidence per year) and endometrial cancer (up to a 10-fold increase in absolute risk) and, therefore, is not recommended ⁸², ⁸³, ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷. The addition of progesterone therapy to estrogen replacement significantly reduces the risk; current combined hormone replacement therapy (HRT) regimens are not associated with an increased risk of endometrial hyperplasia or cancer ⁸², ⁸⁸, ⁸⁹. The current hormone replacement therapy (HRT) regimens add continuous or sequential progestogen therapy to estrogen replacement ⁹⁰, ⁹¹.

Professional organizations including the North American Menopause Society, the British Menopause Society, and the International Menopause Society recommend estrogen replacement therapy for women with premature menopause or premature ovarian failure ⁹², ⁹³, ⁹⁴. There is some evidence, although not from randomized controlled clinical trials, that restoring pathologically low estrogen levels will reduce the later development of cardiovascular disease, osteoporosis, and possibly dementia. This leads to the general recommendation that estrogen be continued in women who experience premature menopause or early menopause until at least around the median age of natural menopause (approximately age 51 years) ¹.

Data are insufficient to evaluate the association between hormone replacement therapy (HRT) or combined hormonal birth control pills administered to women with primary ovarian insufficiency and the risk of developing breast cancer ⁵⁴. Although a number of epidemiologic studies have examined the association between hormone replacement therapy (HRT) in women who are naturally menopausal at midlife and breast cancer risk, demonstrating a 20–30% increased risk of breast cancer in these postmenopausal hormone replacement therapy (HRT) users ⁸², ⁹⁵, these data are not generalizable to women with primary ovarian insufficiency ⁵⁴. Women with primary ovarian insufficiency are much younger at the time of hormone replacement therapy (HRT) initiation and their baseline risk of breast cancer is significantly lower compared with women to whom hormone replacement therapy (HRT) is administered after natural menopause ⁵⁴. Short-term exposure to hormone replacement therapy (HRT) in BRCA1 and BRCA2 gene carriers following risk-reducing bilateral salpingo-oophorectomy has not been associated with an increased risk of developing breast cancer ⁹⁶. Like women with primary ovarian insufficiency, these women are young and require physiologic replacement of hormones. Although reassuring, these data are not a substitute for epidemiologic studies that specifically evaluate the risk of breast cancer in women with primary ovarian insufficiency who are treated with long-term hormone replacement therapy (HRT) ⁵⁴.

Multiple epidemiologic studies have tested the association between combined hormonal birth control pills use in the general population and risk of breast cancer. Overall, the evidence suggests that women who use or have a history of using combined hormonal contraceptives are not at increased risk of breast cancer ⁹⁷, ⁹⁸, ⁹⁹, ¹⁰⁰, ¹⁰¹, ¹⁰², ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶. Although this is reassuring, an even more important question for women with primary ovarian insufficiency is whether long-term use of combined hormonal birth control pills beginning at a relatively young age is associated with breast cancer risk ⁵⁴. Data regarding risk of breast cancer for long-term users are mixed ⁵⁴. In a systemic review of 15 publications addressing this question, five demonstrated an association between oral birth control pill use of at least 5–10 years and breast cancer, whereas the remaining 10 demonstrated no such association ⁹⁷. Meta-analyses have demonstrated no association between long-term oral birth control pill use and breast cancer risk when pooling estimates of multiple studies ⁹⁸, ⁹⁹. More specifically, studies on the association between long-term combined hormonal birth control pill use initiated by nulliparous women younger than 30–45 years and breast cancer risk have yielded mixed results ¹⁰⁰, ¹⁰¹, ¹⁰², ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶, ¹⁰⁷, ¹⁰⁸, ¹⁰⁹, ¹¹⁰; some of the highest-quality population-based case-control studies showed no association ¹⁰², ¹⁰³. Data specifically evaluating the use of combined hormonal contraceptives in women with primary ovarian insufficiency are lacking, so care should be individualized to the needs of each patient ⁵⁴. Women and gynecologists and other health care providers should engage in shared decision making to make the best treatment decision after a discussion of risks and benefits of combined hormonal birth control pill use ⁵⁴.

A common post-pubertal hormone replacement therapy (HRT) regimen is 100 mcg of daily transdermal estradiol or 0.625 mg of daily oral conjugated estrogens, adding 200 mg of micronized oral progesterone daily for 12 days each month ³², ³³, ³⁴. Transdermal estrogen may be associated with lower blood clot (venous thromboembolism) risk than oral formulations ³⁵. It is also reasonable to recommend 1,200 mg of calcium daily and 1,000 IU of vitamin D daily with regular weight-bearing exercises to maintain bone mineral density in accordance with guidelines for postmenopausal women ³⁶, ²⁵.

Hormone replacement therapy (HRT) options

Although exogenous estrogen replacement is recommended for women with primary ovarian insufficiency, data comparing various hormonal regimens for disease prevention, symptom reduction, and safety are lacking in this population ⁵⁴. As a first-line approach, hormone replacement therapy (HRT) either orally or transdermally that achieves replacement levels of estrogen is recommended ⁹⁰, ²⁵, ⁴⁶. However, serum estradiol level testing is not recommended to monitor the effects of treatment ⁵⁴. Estrogen replacement can be achieved with the following estradiol preparations: 1–2 mg oral 17β-estradiol daily, 100 micrograms transdermal 17β-estradiol daily, or conjugated equine estrogens 0.625–1.25 mg daily (see Table 1 below) ²⁵, ⁹⁰, ¹¹¹. The choice of estrogen therapy should be combined with appropriately dosed progestogen therapy (administered continuously or sequentially) to prevent endometrial hyperplasia and cancer. In contrast with continuous progestogen therapy, cyclic administration allows for earlier recognition of a pregnancy. Women with primary ovarian insufficiency may spontaneously ovulate on an infrequent basis, and the absence of a withdrawal bleed should prompt the patient to test for pregnancy ⁵⁴.

Another common approach is the use of combined hormonal birth control pills, which may allow for ease of administration and less patient stigma compared with a hormone replacement therapy (HRT) regimen ⁵⁴. However, the dose of estrogen and progestin in combined hormonal birth control pills is not replacement dosage; these hormonal preparations are significantly more potent than the hormone replacement therapy (HRT) options ⁹⁰. To date, no well-powered randomized trials exist comparing hormone replacement therapy (HRT) with combined hormonal birth control pills in women with primary ovarian insufficiency to determine cardiovascular risk (either coronary artery disease prevention or risk of venous thromboembolism), quality-of-life measures (eg, vasomotor symptoms, bleeding profile, sexual dysfunction, patient satisfaction), or bone health ⁵⁴. Because the replacement doses of estrogen provided in hormone replacement therapy (HRT) are less potent than the estrogen in combined hormonal birth control pills, hormone replacement therapy (HRT) may have a lower risk of blood clot (venous thromboembolism). To further reduce the risk of venous thromboembolism with hormone replacement therapy (HRT), some experts recommend treatment by the transdermal route, eliminating the “first-pass” effect on the liver ³⁵, ¹¹².

Combined hormonal birth control pills prevent ovulation and pregnancy more reliably than hormone replacement therapy (HRT); despite only modest odds of spontaneous pregnancy in women with primary ovarian insufficiency, this is a critical consideration for those who deem pregnancy prevention a priority ⁵⁴. For a woman who prefers noncontraceptive estrogen replacement and wants highly effective contraception, insertion of a levonorgestrel intrauterine device (IUD) is preferable to oral progestin therapy ⁸⁷, ¹¹³. Barrier methods of contraception also may be used. Treatment for all women with primary ovarian insufficiency should continue until the average age of natural menopause is reached (age 50–51 years) ²⁸. Treatment may continue past age 50–51 years if a woman has clinical symptoms or indications ⁵⁴. Regardless of age, the decision to continue hormone replacement therapy (HRT) should be individualized and based on a woman’s symptoms and the risk–benefit ratio ⁵⁴.

Table 1. HRT for premature ovarian failure