What is premature ovarian failure

Premature ovarian failure (also called primary ovarian insufficiency) is the term used to describe the depletion or dysfunction of ovarian follicles with cessation of menses before a woman reaches the age of 40. The term refers to the condition when the ovaries have lost their germinative and hormonal functions because of the exhaustion of the number of ovarian follicles prior to the typical age for physiological menopause, which in Poland averages 51 years ¹. Most probably, premature ovarian failure occurs when the exhaustion of the number of ovarian follicles is concurrent with autoimmune ovarian damage and occurs in association with genetic predisposition. Premature ovarian failure develops in about 1% of women ². The incidence of premature ovarian failure is 1 in 100 women before 40 years of age and 1 in 1000 women before 30 years of age ³.

Premature ovarian failure is not the same as early or premature menopause. With premature menopause, your periods stop before age 40. You can no longer get pregnant. The cause of premature menopause can be natural or it can be a disease, surgery, chemotherapy, or radiation. On the other hand, with premature ovarian failure, some women still have occasional periods. They may even get pregnant. In most cases of premature ovarian failure, the cause is unknown.

“Primary ovarian insufficiency” is the preferred term advocated by the National Institutes of Health because ovarian function is intermittent or unpredictable in many cases. Because 5–10% of women with premature ovarian failure experience spontaneous conception and delivery, premature ovarian failure can be distinguished from natural menopause and also may be described as decreased ovarian reserve ⁴.

Many women with premature ovarian failure do not get monthly menstrual periods, or they have them irregularly, early menopause, an inability to have children (infertility), and elevated levels of a hormone known as follicle stimulating hormone (FSH). Follicle stimulating hormone (FSH) is produced in both males and females and helps regulate the development of reproductive cells (eggs in females and sperm in males). In females, the level of follicle stimulating hormone (FSH) rises and falls, but overall it increases as a woman ages. In younger women, elevated levels may indicate early menopause and fertility problems.

Problems with ovulation may make it difficult for women with premature ovarian failure to get pregnant. In addition, women with premature ovarian failure are at higher risk for certain health conditions, such as osteoporosis, than are women who do not have premature ovarian failure.

The number of reproductive years among women varies, depending on steroid production by the ovaries. There is no consensus on criteria to identify primary ovarian insufficiency in adolescents, and delay in diagnosis is common. Although some adolescent females will report hot flushes or vaginal symptoms like dryness or dyspareunia, the most common presenting symptom of primary ovarian insufficiency is primary or secondary amenorrhea. Among patients with amenorrhea, the incidence of primary ovarian insufficiency ranges from 2% to 10% ⁵. Abnormal bleeding patterns also may include oligomenorrhea (bleeding that occurs less frequently than every 35 days), nonstructural causes of abnormal uterine bleeding (eg, ovulatory dysfunction, iatrogenic, or not yet classified), or polymenorrhea (bleeding that occurs more often than every 21 days) ⁶. Because irregular menstrual cycles are both common during early adolescence and an initial symptom of early primary ovarian insufficiency, diagnosis can be difficult in this population. Although less than 10% of women who present with abnormal menses will ultimately be found to have primary ovarian insufficiency, the condition has such detrimental consequences on bone health that early diagnosis of this condition is important ⁷. Therefore, in young females it is important to evaluate amenorrhea or a change from regular to irregular menses for 3 or more consecutive months in the absence of hormonal preparations such as oral contraceptives for all potential causes, including pregnancy, polycystic ovary syndrome, hypothalamic amenorrhea, thyroid abnormalities, hyperprolactinemia, and primary ovarian insufficiency ⁷. Inquiries should be made about family medical history because females with a family history of early menopause are at risk of primary ovarian insufficiency ⁸.

Other names for premature ovarian failure

• Primary ovarian insufficiency
• Premature menopause
• Premature ovarian failure
• Ovarian hypofunction
• Hypergonadotropic hypogonadism
• Fragile X-associated premature ovarian failure, used to describe premature ovarian failure related to a specific genetic change

What is ovarian reserve?

Clearly, women of the same age can have very different responses to ovarian stimulation and have differing reproductive potential. The concept of ovarian reserve views reproductive potential as a function of the number and quality of remaining oocytes (eggs). Decreased or diminished ovarian reserve describes women of reproductive age having regular menses whose response to ovarian stimulation or fecundity is reduced compared with women of comparable age. Decreased ovarian reserve is distinct from menopause or premature ovarian failure, and also may be described as primary ovarian insufficiency ⁹. Although ovarian reserve tests have been applied widely, debate continues over the ability of tests currently in use to predict three related, but distinctly different, outcomes: oocyte quality, oocyte quantity, and fecundity.

In most cases, the cause(s) of diminished ovarian reserve are unknown. It is unclear whether diminished ovarian reserve represents a pathologic condition resulting from abnormally rapid atresia in a normal pool of oocytes, from normal atresia of an abnormally small initial pool of oocytes, or simply the extreme end of a normal bell-shaped population distribution of the number of oocytes at a given age ¹⁰. A loss of oocytes and fertility potential is associated with exposure to systemic chemotherapy, pelvic irradiation, and genetic abnormalities (e.g., 45,X chromosomal mosaicism, FMR1 (fragile X mental retardation 1) premutations). Diminished ovarian reserve has not been associated with other lifestyle behaviors, with the possible exception of cigarette smoking ¹¹.

What are measures of ovarian reserve?

Ovarian reserve tests include both biochemical tests and ultrasound imaging of the ovaries. Biochemical tests of ovarian reserve can be divided further into basal measurements, including measurement of follicle-stimulating hormone (FSH), estradiol, inhibin B, and antimüllerian hormone, and provocative tests such as the clomiphene citrate challenge test. Biochemical measures of ovarian reserve are intended to probe and to reflect the biology of the aging ovary, the one component of the reproductive system most closely related to decreased fecundity.

Inhibin B and antimüllerian hormone are glycoprotein hormones produced by small ovarian follicles and are therefore direct measures of the follicular pool. Whereas antimüllerian hormone is primarily secreted by primary, preantral, and antral follicles, inhibin B is secreted primarily by preantral follicles. As the number of ovarian follicles declines with age, both antimüllerian hormone and early follicular phase inhibin B concentrations decline. Decreased inhibin B secretion lowers the level of central negative feedback, resulting in increased pituitary FSH secretion and in higher late luteal and early follicular FSH concentrations (an “indirect” measure). In turn, the earlier increase in FSH levels stimulates an earlier onset of new follicular growth and increase in estradiol concentrations, ultimately decreasing the length of the follicular phase and the overall cycle. Dynamic ovarian reserve tests assess the response of the hypothalamic-pituitary-ovarian axis to a stimulus.

Ultrasonographic measures of ovarian reserve include the antral follicle count and ovarian volume. The antral follicle count describes the total number of follicles measuring 2–10 millimeters in diameter that are observed during an early follicular phase transvaginal scan. The number of antral follicles correlates with the size of the remaining follicular pool and the number of oocytes retrieved following stimulation. Ovarian volume declines with age and is therefore another potential indicator of ovarian reserve.

The ovarian reserve is assessed on cycle day 3 through antimüllerian hormone, FSH, antral follicle count, inhibin B, and estradiol testing. Patients with premature ovarian failure have elevated levels of FSH and estradiol (cycle day 3), considerably lower levels of antimüllerian hormone and inhibin B, as well as low antral follicle count levels.

Antimüllerian hormone is produced by the granulosa cells of the preantral follicles. Currently, it is believed that antimüllerian hormone is the best marker to be used to assess the ovarian reserve. FSH levels may vary from cycle to cycle.

It is commonly accepted that FSH levels > 15 IU/l are abnormal, and with FSH being > 20 IU/l the chances of getting pregnant are very unrealistic. According to some data, the ovarian reserve is thought to be diminished even at FSH levels > 10 IU/l. Women with a lower ovarian reserve quite often manifest normal FSH concentrations. For this reason, in order to assess the ovarian reserve, both FSH and antimüllerian hormone levels should be measured ¹².

• Currently, there is no uniformly accepted definition of decreased or diminished ovarian reserve, as the term may refer to three related but distinctly different outcomes: oocyte quality, oocyte quantity, or reproductive potential.
• Available evidence concerning the performance of ovarian reserve tests is limited by small sample sizes, heterogeneity among study design, analyses and outcomes, and by the lack of validated results. The design of published studies must be examined carefully before applying the results in clinical practice.
• A number of different “ovarian reserve tests” have been devised as screening tests to help predict success with IVF. Ideally, the optimal screening test should be reproducible (low inter- and intra-cycle variability) and exhibit high specificity to minimize the risk of incorrectly categorizing women with normal ovarian reserve as having decreased ovarian reserve. A screening test itself cannot diagnose decreased ovarian reserve.
• Overall, FSH is the most commonly used screening test for decreased or diminished ovarian reserve, but antral follicle count and antimüllerian hormone are promising predictors.
• Home tests of ovarian reserve have serious limitations and pitfalls, including the complexity of test interpretation and use in populations at low risk for decreased ovarian reserve, resulting in misinterpretation that provides false reassurance or unnecessary anxiety and concern.

Premature ovarian failure causes

In women with normal ovarian function, the pituitary gland releases certain hormones during the menstrual cycle, which causes a small number of egg-containing follicles in the ovaries to begin maturing. Usually one or two follicles — tiny sacs filled with fluid — reach maturity each month.

When the follicle matures, it opens, releasing an egg. The egg enters the fallopian tube where a sperm cell might fertilize it, resulting in pregnancy.

Premature ovarian failure results from the loss of eggs (oocytes). Follicle depletion or dysfunction in adolescents may be caused by many different factors. Premature ovarian failure is often caused by chromosomal abnormalities or damage from chemotherapy or radiation therapy. It is also associated with a premutation in the FMR1 gene for fragile X. Primary ovarian insufficiency may be associated with multiple endocrinopathies, including hypoparathyroidism and hypoadrenalism. Less frequently, premature ovarian failure can result from infiltrative or infectious processes ⁵. Pelvic surgery also may lead to impairment of ovarian function. Approximately 4% of women who have primary ovarian insufficiency will have adrenal or ovarian antibodies, which suggests an autoimmune mechanism for disease ¹³. In many cases, the cause remains unknown ⁶.

Chromosomal Abnormalities

A common cause of primary ovarian insufficiency in adolescents is gonadal dysgenesis, with or without Turner syndrome ⁵. When adolescents present with primary amenorrhea and no associated comorbidities, 50% are found to have abnormal karyotypes. Among younger women (aged 30 years or younger) with secondary amenorrhea, 13% also have been noted to have an abnormal karyotype ¹⁴. Although pubertal and growth delays are common in this group, many affected females may first be recognized at the time of evaluation for menstrual abnormalities.

Chemotherapy and Radiation Therapy

The immediate loss of ovarian function after chemotherapy or radiation therapy is termed “acute ovarian failure,” which may be transient. With chemotherapy, the age of the patient when she received chemotherapy, types of medication, and number of doses all have an effect on the possibility of gonadotoxicity. Although the highest incidence of acute ovarian failure occurs after the use of alkylating agents or procarbazine, the younger the patient at the time of receiving the chemotherapy, the more likely it is that some follicles will survive ¹⁵. Whole-body, whole-brain, pelvic, and spinal irradiation also increase the risk of acute ovarian failure ¹⁶. Pelvic irradiation (especially doses more than 10 Gy) is a significant risk factor for acute ovarian failure ¹⁵. Chemotherapy combined with radiation therapy increases the chance of acute ovarian failure. It should be noted that even females who menstruate after chemotherapy have an increased lifetime risk of primary ovarian insufficiency ¹⁶.

Fragile X Syndrome

Fragile X syndrome is the most common form of hereditable mental retardation. Among females with primary ovarian insufficiency and a normal karyotype, 6% have a premutation in the FMR1 gene ¹⁴. Although the onset of menstruation appears to be normal among premutation carriers in adolescence, approximately 1% of premutation carriers will experience their final menses before age 18 years ¹⁷. If a woman has a personal or family history of ovarian failure or an elevated follicle-stimulating hormone (FSH) level before age 40 years without a known cause, fragile X premutation carrier testing should be offered ¹⁸.

An immune system response to ovarian tissue (autoimmune disease)

In this rare form, your immune system produces antibodies against your ovarian tissue (anti-ovarian antibodies), harming the egg-containing follicles and damaging the egg, but their specificity and pathogenic usefulness has not been validated ¹⁹. What triggers the immune response is unclear, but exposure to a virus is one possibility.

Patients with premature ovarian failure can develop concomitant autoimmune diseases, such as autoimmune thyroiditis (Hashimoto’s disease), autoimmune adrenal insufficiency (Addison’s disease), diabetes type 1, celiac disease, albinism, rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis ²⁰.

Premature ovarian failure can be part of the autoimmune polyglandular syndrome. For this reason, in order to diagnose the former, it is necessary to determine whether the patient presents with other autoimmune endocrine disorders ²¹ because as it has been proven that premature ovarian failure is likely develop 8-14 years before Addison’s disease does ²².

The autoimmune pathogenesis is a multistage process. In this case, genetic and environmental factors must occur. The pathogenic mechanism has been thoroughly investigated in animal models of insulitis and thyroiditis ²³. First, abnormal amounts of dendritic cells accumulate in the endocrine tissue. Then, autoreactive CD4+ and CD8+ lymphocytes, which are a source of IgG autoantibodies, are produced in an uncontrolled manner. Autoreactive T lymphocytes cause damage to the gland tissue. Patients with autoimmune thyroid diseases (Graves’ disease and Hashimoto’s disease) have been shown to have increased amounts of macrophage cells and NK cells with MHC class II molecules (histocompatibility complex class II) in the thyroid gland ²⁴, and increased IgG levels in blood ²⁵.

Unknown factors

It’s possible to develop premature ovarian failure, but have no known chromosomal defects, toxin exposure or autoimmune disease. Your doctor might recommend further testing to find the cause, but in most cases, the cause remains unknown (idiopathic).

Risk factors for premature ovarian failure

Factors that increase your risk of developing premature ovarian failure include:

• Age. Risk rises between the ages of 35 and 40, although younger women and adolescents can develop the condition.
• Family history. Having a family history of premature ovarian failure increases your risk of developing this disorder.
• Multiple ovarian surgeries. Ovarian endometriosis or other conditions requiring repeated surgeries on the ovaries increases the risk of premature ovarian failure.

Premature ovarian failure complications

Complications of premature ovarian failure include:

• Infertility. Inability to get pregnant may be the most troubling complication of premature ovarian failure, although in rare cases, pregnancy is possible until the eggs are depleted.
• Osteoporosis. The hormone estrogen helps maintain strong bones. Women with low levels of estrogen have an increased risk of developing weak and brittle bones (osteoporosis), which are more likely to break than healthy bones.
• Depression or anxiety. The risk of infertility and other complications arising from low estrogen levels causes some women to become depressed or anxious.
• Heart disease. Early loss of estrogen might increase your risk.
• Dementia. Lack of estrogen can contribute to this in some people.

Premature ovarian failure symptoms

Missed periods are usually the first sign of premature ovarian failure. Later symptoms may be similar to those of natural menopause:

• Hot flashes
• Night sweats
• Irritability
• Poor concentration
• Decreased sex drive
• Pain during sex
• Vaginal dryness

Premature ovarian failure diagnosis

Most women have few signs of premature ovarian failure. Diagnosis usually involves a physical exam, including a pelvic exam. Your doctor might ask questions about your menstrual cycle, exposure to toxins, such as chemotherapy or radiation therapy, and previous ovarian surgery.

Your doctor might recommend one or more of these tests:

• Pregnancy test. This checks for an unexpected pregnancy in a woman of childbearing age who has missed a period.
• Follicle-stimulating hormone (FSH) test. FSH is a hormone released by the pituitary gland that stimulates the growth of follicles in your ovaries. Women with premature ovarian failure often have abnormally high levels of FSH in the blood.
• Estradiol test. The blood level of estradiol, a type of estrogen that comes from the ovaries, is usually low in women with premature ovarian failure.
• Prolactin test. High blood levels of prolactin — the hormone that stimulates breast milk production — can lead to problems with ovulation, including irregular or absent menstrual periods.
• Karyotype. This test examines your 46 chromosomes for abnormalities. You could have only one X chromosome instead of two or other chromosomal defects.
• FMR1 gene testing. The FMR1 gene is the gene associated with fragile X syndrome — an inherited disorder that can cause intellectual problems. The FMR1 test looks at both of your X chromosomes to make sure they appear normal.

Diagnosis and Initial Evaluation of Primary Ovarian Insufficiency

Diagnosis of premature ovarian failure:

• Menstrual irregularity for at least 3 consecutive months
• Follicle-stimulating hormone and estradiol levels (two random tests at least 1 month apart)
• Prolactin and thyroid function test

If diagnosis is confirmed:

• Karyotype
• FMR1 permutation
• Adrenal antibodies:
  • 21-hydroxylase (CYP21) by immunoprecipitation or
  • Indirect immunofluorescence
• Pelvic ultrasonography

Initial laboratory evaluation for suspected primary ovarian insufficiency includes measurements of basal FSH and basal estradiol levels and tests to rule out causes such as pregnancy, thyroid disease, and hyperprolactinemia. Gonadotropin and estradiol values may be altered by concomitant use of hormonal preparations and thus should only be obtained in patients who are not taking hormonal medications, including oral contraceptives. If gonadotropins are elevated into the menopausal range (typically, basal FSH levels will be greater than 30–40 mIU/mL, depending on the laboratory used), a repeat FSH measurement is indicated in 1 month. If the result indicates that FSH is elevated, a diagnosis of primary ovarian insufficiency can be established. Estradiol levels of less than 50 pg/mL indicate hypoestrogenism.

Antimüllerian hormone and inhibin B are being evaluated to determine their value in the diagnosis of primary ovarian insufficiency. With further research, antimüllerian hormone testing may become increasingly valuable in assessing ovarian reserve before and after chemotherapy for young women with cancer, before and after ovarian surgery, and for females at high risk of primary ovarian insufficiency ²⁶. However, there is significant variability in inhibin B levels between menstrual cycles. This marker does not reliably predict a poor response to ovarian stimulation, and thus, inhibin B is not a recommended test.

Surrogate markers of ovarian reserve (presence of regular menses, serial serum estradiol levels, and antral follicle count by transvaginal ultrasonography) are highly variable and are not predictive of future fertility or hormonal production in young women who have undergone treatment for cancer ²⁷, but are currently undergoing investigation. Once a diagnosis of primary ovarian insufficiency is established, further testing, including karyotype, adrenal antibodies, FMR1 premutation, and pelvic ultrasonography, may be indicated to investigate possible etiologies of primary ovarian insufficiency.

Premature ovarian failure treatment

Treatment for premature ovarian failure usually focuses on the problems that arise from estrogen deficiency. Your doctor might recommend:

• Estrogen therapy. Estrogen therapy can help prevent osteoporosis and relieve hot flashes and other symptoms of estrogen deficiency. Your doctor typically prescribes estrogen with the hormone progesterone, especially if you still have your uterus. Adding progesterone protects the lining of your uterus (endometrium) from precancerous changes caused by taking estrogen alone. The combination of hormones can cause vaginal bleeding again, but it won’t restore ovarian function. Depending on your health and preference, you might take hormone therapy until around age 50 or 51 — the average age of natural menopause. In older women, long-term estrogen plus progestin therapy has been linked to an increased risk of heart and blood vessel (cardiovascular) disease and breast cancer. In young women with premature ovarian failure, however, the benefits of hormone therapy outweigh the potential risks.
• Calcium and vitamin D supplements. Both are important for preventing osteoporosis, and you might not get enough in your diet or from exposure to sunlight. Your doctor might suggest bone density testing before starting supplements to get a baseline bone density measurement. For women ages 19 through 50, the Institute of Medicine recommends 1,000 milligrams (mg) of calcium a day through food or supplements, increasing to 1,200 mg a day for women age 51 and older. Scientists don’t yet know the optimal daily dose of vitamin D. A good starting point for adults is 600 to 800 international units (IU) a day, through food or supplements. If your blood levels of vitamin D are low, your doctor might suggest higher doses.

For adolescents with primary ovarian insufficiency, the objective of treatment is to replace the hormones that the ovary would be producing before the age of menopause, making the treatment distinctly different from hormonal therapy for menopause that focuses on the treatment of menopausal symptoms. The goals of hormonal therapy extend beyond simply symptom relief to levels that support bone, cardiovascular and sexual health. Regardless of the etiology, patients with primary ovarian insufficiency are estrogen deficient. Thus, young women with primary ovarian insufficiency may need higher doses of estrogen than menopausal women to ensure adequate replacement and optimal bone health ⁷. In girls with absent or incomplete breast development, estrogen therapy should be initiated and increased slowly before administration of graduated progesterone dosages until breast development is complete to prevent tubular breast formation. For those patients who have not initiated or completed pubertal growth and sexual maturity, consultation with a specialist in growth and development and hormonal therapy in children is recommended.

Once pubertal development is complete, ongoing hormonal therapy will be necessary for long-term health. Hormonal support involves daily therapy with the goal of maintenance of normal ovarian functioning levels of estradiol. Transdermal, oral, or occasionally transvaginal estradiol in doses of 100 micrograms daily is the therapy of choice to mimic a physiologic dose range and to achieve symptomatic relief. The addition of cyclic progesterone for 10–12 days each month is protective against endometrial hyperplasia and endometrial cancer, risks of unopposed estrogen. Oral estradiol may be used, but it increases the potential for thromboembolism relative to transdermal estradiol due to the first-pass effect on the liver. Oral contraceptives contain higher doses of estrogen than are necessary for hormonal therapy; therefore, they are not recommended as first-line hormonal therapy.

Addressing infertility and contraception

There’s no treatment proved to restore this common complication of premature ovarian failure. It’s important to understand and grieve for this loss of ovarian function and to seek counseling if you need it.

Fertility may persist even when few functional follicles are present. Because of occasional spontaneous resumption of ovarian function, there is a 5–10% chance of spontaneous pregnancy despite a diagnosis of primary ovarian insufficiency ¹⁷. Unless pregnancy is desired, a discussion of effective contraception should take place. Although oral contraceptives are commonly prescribed in this situation, the use of barrier methods or an intrauterine device is encouraged ⁶. If a patient chooses a nonestrogen method of contraception, estrogen also should be administered to preserve bone mineral density and prevent other adverse effects of hypoestrogenemia. A missed menstrual cycle should warrant a pregnancy test.

Some women and their partners pursue a pregnancy through in vitro fertilization (IVF) using donor eggs. The procedure involves removing eggs from a donor and fertilizing them with your partner’s sperm in a lab. The fertilized egg (embryo) is then placed in your uterus.

Lifestyle and home remedies

Learning that you have premature ovarian failure may be emotionally difficult. But with proper treatment and self-care, you can expect to lead a healthy life.

• Learn about alternatives for having children. If you’d like to add to your family, talk to your doctor about options such as in vitro fertilization using donor eggs or adoption.
• Talk with your doctor about the best contraception options. A small percentage of women with premature ovarian failure do spontaneously conceive. If you don’t want to become pregnant, consider using birth control.
• Keep your bones strong. Eat a calcium-rich diet, do weight-bearing exercises such as walking and strength-training exercises for your upper body, and don’t smoke. Ask your doctor if you need calcium and vitamin D supplements.
• Keep track of your menstrual cycle. If you miss a period while taking hormone therapy that causes you to have a monthly cycle, get a pregnancy test.

Coping and support

If you’d hoped for future pregnancies, a diagnosis of premature ovarian failure can bring on overwhelming feelings of loss — even if you’ve already given birth. Grieving is normal.

• Be open with your partner. Talk with and listen to your partner as you both share your feelings over this unexpected change in your plans for growing your family.
• Explore your options. If you don’t have children and want them, or if you want more children, look into alternatives to expand your family, such as donor-egg in vitro fertilization or adoption.
• Seek support. Talking with others who are going through the same thing can provide valuable insight and understanding during a time of confusion and uncertainty. Counseling might help you adjust to your circumstances and the implications for your future. Ask your doctor about national or local support groups or seek an online community as an outlet for your feelings and a source of information.
• Give yourself time. Coming to terms with your diagnosis is a gradual process. In the meantime, take good care of yourself by eating well, exercising and getting enough rest.

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