Premature ovarian insufficiency

Synonym: premature ovarian failure

What is premature ovarian insufficiency?

Premature ovarian insufficiency (POI) occurs in women aged under 40 years and is a syndrome consisting of amenorrhoea, elevated gonadotrophins and oestrogen deficiency due to the transient or permanent loss of ovarian function.

Epidemiology

• At least 1% of women under the age of 40 are affected.

• The term premature ovarian insufficiency encompasses both spontaneous POI and POI which occurs as a result of iatrogenic interventions.¹

• 0.1% of women aged under 30 and 0.01% of women aged under 20 are affected.

Aetiology

• Premature ovarian insufficiency does not always develop by the same mechanism as the normal menopause, which is a result of follicle depletion.

• POI can be due to an autoimmune, genetic or iatrogenic cause, but most cases are idiopathic.²

• Some women develop POI due to mutations in the follicle-stimulating hormone (FSH) receptor.³

• Numerous studies have demonstrated the presence of mutations and polymorphisms in genes associated with development, recruitment and oocyte atresia in women with POI.⁴

• Iatrogenic POI is the most common known cause of POI:

  • Surgical removal of ovaries and hysterectomy.

  • Radiotherapy.

  • Chemotherapy - this can be temporary, as recovery of ovarian function can occur, especially in younger women.⁵

• There is a family history of POI in around 20-30% of cases.⁶

• X-linked chromosomal abnormalities (eg, Turner syndrome) occur in around 13% of women with POI. They are more frequent in those who present with primary amenorrhoea (in around 50% of women).

• Another cause of POI is steroidogenic cell autoimmunity lymphocytic oophoritis which is a specific autoimmune attack against growing ovarian follicles.⁷ There is often a family history of autoimmune conditions in these women.

• POI may be associated with various infections such as:

  • Mumps.

  • Tuberculosis.

  • Malaria.

  • Chickenpox.

  • Cytomegalovirus.

• Cigarette smoking and being underweight class are associated with increased risk of POI. ²

• Later menarche, irregular menstruation and longer breastfeeding all provide protection from POI.⁸

Premature ovarian insufficiency symptoms

• The most common symptoms of premature ovarian insufficiency are primary or secondary amenorrhoea - POI should be suspected in any woman who presents with secondary amenorrhoea of more than three months' duration..³

• However, abnormal bleeding patterns also include oligomenorrhoea.

• Hot flushes and vasomotor symptoms may be present but around 25% of women do not have these symptoms.¹

• Amenorrhoea may develop after a pregnancy or after cessation of hormonal contraceptives - this does not mean that it was caused by the use of that hormonal contraception.

• POI can affect many women psychologically. They can experience feelings of anger, guilt, sadness and helplessness, particularly if they do not feel that their family is complete. Relationship difficulties can occur. Signposting to organisations such as The Daisy Network can help.

Investigations

• FSH levels should be taken. Two samples, 4-6 weeks apart.

• Two raised levels (more than 30 IU/L) are diagnostic.^{9 2}

• Women with POI have a low estradiol (usually <50 pmol/L).

• Serum LH, estradiol, testosterone, TFTs and prolactin levels may also be useful. ²

• A dual-energy X-ray absorptiometry (DXA) bone scan should be requested for anyone with an untreated premature menopause.¹⁰

• Anti-Müllerian hormone may be a measure of reduced ovarian reserve but should only be requested from secondary care - for example, if being seen at a fertility clinic. It is not part of the routine assessment of someone with POI.^{11 12}

• Testing for adrenal antibodies, karyotype and the FMR1 gene premutation are the main diagnostic tests currently available to determine an underlying aetiology.¹

• Fragile X testing should be performed in those presenting at a young age or those with a family history of POI or learning difficulties.

• Screening for other autoimmune diseases is often recommended. POI is frequently associated with hypothyroidism, Addison's disease and diabetes mellitus.

• Other investigations may be undertaken to identify any underlying cause for the diagnosis. These may include a transvaginal ultrasound scan.

• It may be appropriate to refer relatives of some women with spontaneous POI for genetic counselling.

Premature ovarian insufficiency treatment

• Women with POI should be managed by a professional with the experience to help manage all aspects of the physical and psychological aspects of the condition. Depending on local expertise, that professional may be in primary or secondary care.⁹

• Women with POI may have complex physical and psychological needs and a multidisciplinary approach may be appropriate.³

• Some women may need referral to a psychologist or psychiatrist.

• Any associated depression or anxiety needs to be addressed and managed appropriately.

• General lifestyle and dietary measures to reduce the risk of cardiovascular disease and osteoporosis should be undertaken.

• d.

• Women with POI should almost always be given sex steroid replacement until at least the average age of the menopause (51 years). This is not just for symptom control but also to maintain their long-term health. Women taking HRT should be reviewed at the average age of the natural menopause (around 51 years) and a further discussion regarding the benefits and risks of HRT should be undertaken. One possible exception to this is women who have previously had breast cancer - written advice should be obtained from their oncologist before considering HRT.

• Replacement may be with HRT or the combined oral contraceptive.

• Treatment with HRT can be given sequentially to induce a regular withdrawal bleed or as a continuous combined preparation to achieve amenorrhoea. Continuous combined preparations should not be started within one year of the last period as this may lead to irregular bleeding.

• HRT will maintain age-appropriate bone density and also significantly reduce the risk of fracture. However, women with POI will generally require higher doses of oestrogen to achieve symptom relief compared to postmenopausal women.

• If using combined hormonal contraception (CHC) for sex hormone replacement, it should be noted that CHC is associated with an increased risk of venous thromboembolism (VTE) - safety should be assessed using the UK Medical Eligibility Criteria as for any women using contraception.¹³ Using CHC continuously, or with a shorter hormone-free interval than the standard seven days, is now accepted practice and can be recommended for women with POI.

• For many women who still require contraception, the combination of oestrogen with an intrauterine system (IUS) is often an optimal combination.

• Egg donation is often required for women who wish to attempt conception.

Complications

• Women with POI have a significantly increased risk of osteoporosis, cardiovascular disease and possibly Alzheimer's disease. Women with POI have worse cognitive function with increased risk of poor verbal fluency and impaired visual memory.

• Women with POI have significantly lower bone mineral density and increased fracture risk. The period of accelerated bone loss occurs during the initial 4-5 years after the menopause.

• There is around an 80% increase in risk of mortality from coronary heart disease in those with menopause aged under 40 compared with women with menopause aged 49-55. Studies have demonstrated an 80% increased risk of mortality from coronary heart disease in women who do not take HRT.¹

• Spontaneous pregnancies can occur in 5-10% of women with POI, as a result of intermittent ovarian function and so contraception remains important if they do not wish to conceive.¹

Prognosis

Sex steroid replacement for women with POI up to the normal age of natural menopause will not only improve symptoms but also reduce the risk of osteoporosis and cardiovascular disease.