Primary ovarian insufficiency

Most women experience the natural end ovarian function, the event we call menopause, between 45 and 55 years of age. This age range reflects the individual variation in biological ageing of the ovaries between different women.

Primary ovarian insufficiency, also called ‘POI’, occurs when a woman’s ovaries are no longer able to produce an egg before a woman has turned 40 years old.

When this occurs the amount of hormones the ovaries make drops suddenly so that women have low levels of the hormones oestrogen, progesterone and testosterone.

The onset of POI is not always sudden. Many women experience intermittent ovarian function after their periods initially stop. Therefore, some women’s ovaries will randomly produce hormones and may ovulate, even though they have had blood tests showing that their ovaries have stopped functioning. Pregnancies have occasionally occurred after the diagnosis of POI has been made.

POI affects approximately:

  • 1/1000 women aged 15-29 years
  • 1/100 women aged 30-39 years

We often talk about POI as being

  1. Primary: This is when a woman has never had menstrual cycles.
  2. Secondary: This is when menstruation occurs for months to years, but then stops before the age of 40 because the ovaries have stopped fully functioning.

Symptoms of POI

The age at which POI occurs is dependent on the underlying cause as well as the timing and speed of loss of ovarian function.

POI occurring before puberty results in failure of sexual development and menstruation does not occur.

  • Girls who develop POI before puberty do not experience the classic symptoms of oestrogen deficiency as exposure of the body to adult levels of oestrogen and subsequent oestrogen loss appear to be necessary for these symptoms to occur.

POI after puberty

  • Some girls experience full sexual development followed by one or two menstrual cycles before the ovaries stop working- they may have just a small amount of ovarian tissue which functions briefly.
  • Often young women who develop POI after puberty experience hot flushes, night sweats, fatigue and mood changes including emotional lability, irritability and depression due to insufficient oestrogen. Vaginal dryness and discomfort with intercourse are also common features of oestrogen lack.
  • Women with POI not only suffer from low oestrogen and progesterone but also from low of testosterone. In the past testosterone was considered as a ‘male’ hormone but we now know it is also important in women, being produced by both the adrenal glands and the ovaries.

Causes of POI

  • Spontaneous – In most cases there is no identifiable cause of POI. In this situation it is described as spontaneous. Up to 1 in 3 women woman with spontaneous POI to have a family history of early menopause in either their mother or sister.
  • Autoimmune – This is when there is an immune attack on the ovaries. About one quarter of women who have autoimmune POI may also have/ develop an underactive thyroid hypothyroidism). Much less commonly POI is associated with underactive adrenal glands (2.5%) and diabetes (2.5%), and sometimes other hormonal problems.
  • Genetic disorders – Females have two X chromosomes. The genetic changes causing POI usually are associated with an abnormality of the long arm of one of these X chromosomes.
    • Chromosomal abnormalities are found in 40-50% of women who never experience normal puberty.
    • Absence or damage to the X chromosome(s) may lead to the cells of the ovaries never developing develop properly. If they stop developing before birth the ovaries are replaced by a white thin fibrous streak and is known as a ‘streak gonad’.
    • Women less than 160cm tall are more likely to have a chromosomal defect.
    • When chromosomal abnormalities are found, the diagnosis of POI can be made with certainty.
    • The most common genetic abnormality causing POI is a condition known as Turner's syndrome in which there is only one X chromosome instead of two. Many women with Turner’s syndrome appear to enter puberty normally. However it is more common for affected girls not to experience puberty and need hormone therapy to develop of breasts and body hair, and fully develop healthy bones.
  • Fragile X premutation – Recently, changes in a part of the X chromosome that codes a gene called FMR1 has been associated with POI. Extreme changes in this gene can result in autism, subtle changes are associated with POI and may explain up to 13% of familial cases and 3% of sporadic cases of POI. Today an FMR1 gene screen should be performed as part of assessment of POI

All women who experience POI before the age of thirty years must have a blood test for chromosomal assessment. This is because occasionally, in addition to having an abnormality in an X chromosome, some women may have an inactive Y chromosome in their genetic material. The presence of a Y chromosome in this case is associated with a substantial risk of future cancer of the undeveloped ovaries. It is advised in this case the ovaries or ovary–like tissue, surgically removed to eliminate their considerable risk of developing cancer.

Cancer therapy as a cause of POI: Women who have had radiotherapy of the pelvis and chemotherapy may experience an early menopause as the ovaries are extremely sensitive to the effects of radiation. The radiation dose which causes complete ovarian failure depends on the number of eggs present in the ovaries, which usually is determined by a woman's age. In women over the age of forty years, a radiation dose to the ovary greater than 600 Rads will usually result in ovarian failure. In contrast, younger women who have had up to 3000 Rads to the pelvis have gone on to conceive. Radiation is more toxic to the ovaries than chemotherapy, therefore when the two treatments are combined, ovarian failure is more commonly due to the radiation exposure.

An important factor in the development of POI is the position of the ovaries in relation to the radiotherapy field. Thus, some women may have their ovaries moved surgically so that they are out of the range of the radiation area.

The likelihood of developing ovarian failure after chemotherapy depends on the age at treatment, drug type, dose, and duration of treatment. In general, younger women are more resistant to the ovarian effects of chemotherapeutic agents than older women. In some younger women ovarian function returns after a period of loss of periods and menopausal symptoms.

Galactosemia occurs due to a deficiency in the enzyme galactose-1-phosphate uridyl transferase (GALT). It is a rare autosomal recessive disorder with some people being severely affected. Most women with galactosemia develop POI.

Infectious agents: Mumps oophoritis has been implicated as a rare cause of POF. However, patients with mumps oophoritis should be reassured that in most cases following recovery of the mumps normal ovarian function is expected to resume. Ovarian failure has also been reported to occur following Shigella infections, malaria, and varicella, but a cause and effect relationship has not been established.

Surgical menopause: Women who have both their ovaries removed are by definition postmenopausal.

Diagnosis of POI

Young women who do not menstruate by the age of seventeen years or who stop menstruating for more than six months should be formally assessed in order to identify the underlying cause.

There are several reasons why periods might not occur or might stop ranging from abnormal gynaecological anatomy through to stress or hormonal imbalances.

Measurement of hormones is the key to diagnosis, but;

  • POI cannot be diagnosed on a single blood test. A low oestrogen level PLUS a high FSH level must be detected on at least three separate occasions each at least one month apart for a firm diagnosis to be made.
  • Chromosomal analysis is essential for all women experiencing POI before the age of thirty years.

Older women should discuss the option of chromosomal studies, as identification of an abnormality may influence other family members, sisters or daughters, who carry the same defect in terms of planning pregnancies.

POI and hormone therapy

All women who experience POI require long term hormone therapy (HT) in order to maintain good overall health. In addition to the loss of fertility, women with POI are at high risk of bone loss and developing early osteoporosis. The earlier the loss of normal levels of ovarian hormones, the greater the risk of bone loss.

POI is also associated with increased risk of developing cardiovascular disease in midlife.

HT in this instance is not a controversial issue and is not comparable to the use of HT after menopause after the age of 50 years.

Women who experience early loss of ovarian function are relatively oestrogen, progesterone and testosterone deficient when compared to other normal women of the same age. Taking HT for POI is generally considered no different to someone with an under active-thyroid taking thyroid hormone replacement or a diabetic using insulin. Whether or not women with POI choose to continue using HT beyond the average age of natural menopause, fifty–one years, is a different issue.

Many people consider HT with estradiol and progesterone to be the best as these are the actual hormones that are not being made. Often however young women prefer to use the oral contraceptive pill because of ease of use and not wanting to appear different from their friends. The most important things are to;

  1. Take enough oestrogen to prevent bone loss- usually more than standard postmenopausal hormone therapy
  2. To continue hormone therapy until the average age of menopause (51 years)


Infertility is probably the most distressing consequence of POI. For women with specific causes of POI the likelihood of fertility is remote and for women with streak ovaries or surgical premature menopause, infertility is absolute. No therapies have been demonstrated to be effective in restoring fertility in women with POI.

In most instance by the time spontaneous POI is diagnosed, the ovaries have no eggs left. When FSH is found to be greater than 100 u/l ovarian failure is probably permanent and irreversible. Very rarely, when spontaneous POI is diagnosed early there may be a few healthy nests of eggs left in the ovaries, although they are immature and their numbers are insufficient to produce much in the way of sex hormones. Infrequently, one of these remaining eggs unpredictably responds to the stimulation of high blood brain FSH levels, oestrogen production switches on and the egg starts to develop. In most instances when this happens the development of the egg is flawed and ovulation does not occur. Rarely however, ovulation may happen spontaneously, usually in women with low levels of FSH.

Thus the possibility of a pregnancy in young women suffering spontaneous POI is less remote than previously believed with a 10 to 15 percent life time chance of conception. Successful pregnancy is usually limited to women taking hormone therapy (HT). This is because without hormones, the lining of the uterus is undeveloped and unreceptive to a fertilised egg. Women taking HT are more likely to have a uterus with a suitable lining for implantation of a fertilised egg and an ongoing pregnancy. Blood levels of hormones are poor predictors of ovulation. However, ovulation and conception are more common in women with one or two FSH measurements below 40 u/l.

Disproven treatments include oestrogens, anti–oestrogens, gonadotrophin therapy and the drugs Danazol, Clomiphene citrate and Bromocriptine. Thus, any attempts to induce ovulation should be restricted to specific controlled clinical trials.

The first report of a successful pregnancy with the delivery of a healthy baby in a woman with POI through oocyte (egg) donation was in 1984. Oocyte donation is an option for women with POI with pregnancy rates being reported by some groups to be as good or better than in vitro fertilisation. The rates vary between different infertility treatment centres and with the specific programs used. Oocyte donation is a physically and emotionally demanding process as it involves monitoring egg development, egg retrieval from the donor, fertilisation outside the body (test tube fertilisation) implantation of the embryo into the women desirous of the pregnancy and a receptive uterus for the implanted embryo.

Disclaimer: The above information is a general guide and was accurate at the time of production of this page. This information is designed to complement, not replace, the advice of your health professional.