Premature Ovarian Failure

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What is Premature Ovarian Failure (POF)?

Premature ovarian failure (POF), or premature menopause, refers to the loss of ovarian function in women prior to the age of 40. As the ovaries stop working, estrogen levels fall, and the brain produces more FSH (follicle stimulating hormone), trying to force the ovaries to continue working. The periods become irregular and eventually stop, leading to signs and symptoms of menopause. The average age of natural menopause is approximately 51 years (range 40 to 55 years). 

Approximately 1% of reproductive aged women have POF. In a province like BC, for example, there are about 8000 women with POF.

There are a number of known causes of POF (Table 1), such as chemotherapy, radiation and inherited conditions like Turner Syndrome and Fragile X. Other factors, such as cigarette smoking are known to lower the age of normal menopause, often by two to three years or more. However, for nearly two-thirds of cases, the cause remains unknown. Between five and 30% of women with POF will have at least one other affected relative, usually a sister or mother. Regardless of the underlying reason, POF occurs when the ovaries run out of eggs, or when something happens to make the remaining eggs unresponsive.

Chromosomal or genetic conditions, especially those involving the X chromosome, can result in a very small supply of eggs, or rapid depletion of the supply. Some types of chemotherapy or radiation to the ovaries can cause rapid destruction of the eggs. Surgical removal of both ovaries results in POF, as can extensive ovarian surgery (i.e. for the removal of large bilateral cysts), especially if large amounts of ovarian tissue are removed or if the ovarian blood supply is compromised.

Many women with POF have autoimmune disorders (such as thyroid problems, lupus, diabetes, rheumatoid arthritis etc), or have a strong family history of these conditions. Autoimmune conditions occur when the immune system gets mixed signals and produces antibodies against a certain part of the body (such as the thyroid gland, the pancreas, the joint linings etc). While we don’t have a precise antibody to measure in women with POF, the high incidence of associated autoimmune disorders suggests that some cases of POF may be due to an autoimmune disorder that doesn’t actually destroy the eggs, but makes them unresponsive and unable to ovulate. The severity of autoimmune conditions can wax and wane, and so can POF, allowing some women to enter into a “remission”.

About 10-20 percent of women with POF will enter into a remission where ovarian function returns. Menstrual periods return and relief of menopausal symptoms may occur. Ovulation and pregnancy is possible. Pregnancies occur after a diagnosis of POF in five to ten percent of women. Unfortunately, we have no way of predicting who will have remissions, when they will happen or how long they will last. As well, we do not have a reliable way of inducing a remission, although this is the subject of much research. Women whose ovaries have run out of eggs are not likely to go into remission. However, it seems that remissions are possible in some women (i.e. those with autoimmune disorders) who still have normal numbers of eggs, even though they’ve become unresponsive.

Good question … but this is very difficult to assess easily or accurately. Removing an ovary and examining it under the microscope is the most accurate way, but is too invasive and drastic for routine use. Ovarian biopsies are not particularly accurate because they test only a small portion of the ovary. Other tools such as transvaginal ultrasound are being investigated to see if they may be helpful.

Women with POF may have any of the natural signs and symptoms of menopause. These include irregular or absent periods, hot flashes, night sweats, sleeping problems, mood swings, problems with concentration or memory, vaginal dryness, painful intercourse, low sex drive, loss of energy, etc. Often, the symptoms are more severe in young women than in women who go through the menopause in their 50’s.

The diagnosis of POF usually requires at least three months without a period and two elevated FSH blood tests at least one month apart. Depending on the lab, normal FSH levels are usually less than 10-15 IU/L, while elevated levels are greater than 20-40 IU/L.

Many young women find menopausal symptoms quite bothersome. Women with POF who are not taking estrogen have a higher risk of bone loss (osteoporosis) and cardiovascular disease. Some of the inherited, metabolic or autoimmune conditions that occur in association with POF may have an impact on health, and require individual evaluation and treatment. Women with POF are generally unable to conceive unless they go into remission or use donor eggs. Loss of fertility is often the most distressing aspect of POF and may give rise to depression, guilt and the feeling of being less feminine.

Hormone replacement therapy (HRT) containing estrogen and progesterone is often used to treat menopausal symptoms and prevent osteoporosis. Birth control pills are sometimes substituted for hormone replacement therapy. At this point in time, there is no reliable treatment to induce a remission or restore fertility for someone diagnosed with POF. Pregnancies can occasionally occur during spontaneous remissions. However, the only reliable way of achieving a pregnancy is to use donor eggs, obtained during an IVF cycle from a young healthy donor who may be known to the recipient or who may be an anonymous egg donor.

In order to stimulate the ovaries with fertility drugs, the ovaries have to have healthy functioning eggs and follicles (the fluid-filled cavity where the egg grows). Fertility drugs are primarily made up of FSH. Since we already know that menopausal ovaries are not responding to the body’s natural high levels of FSH, further FSH found in fertility drugs will not make a difference.

The diagnosis of POF can have a profound emotional impact. Because it’s not a particularly common condition, it can be difficult for women with POF to find others with similar concerns. Local and national infertility support groups such as IAAC provide invaluable support and general information. 

For more specific resources, the POF Support Group (www.pofsupport.org) was established to provide support and information to women with POF, to increase public awareness and understanding of POF and to work with health care professionals to better understand this condition. In addition to a quarterly newsletter called “Endless Possibilities”, their website hosts various discussion groups and offers factual medical information, reading lists and useful links.

ABOUT THE AUTHORS: Susan McKeachie BSN and Margo Fluker MD, FRCSC are currently completing a large POF research project. They also provide reproductive endocrinology, infertility and assisted reproduction services through the Genesis Fertility Centre in Vancouver, where Dr. Fluker is a co-director.