What is the Best Management Strategy for a 20-year-old Woman With Premature Ovarian Failure?

Melanie C. Davies; Beth Cartwright

Disclosures

Clin Endocrinol. 2012;77(2):182-186. 

In This Article

Investigations

Investigations should be offered at the first visit to a specialist to confirm the diagnosis if necessary, to discover the cause of POF and to identify any associated medical conditions.

Confirmation of Diagnosis

The diagnosis of POF is usually confirmed by the combination of a 6-month period of amenorrhoea or oligomenorrhoea and two measurements of follicle-stimulating hormone (FSH) above 30 IU/l taken at least 4 weeks apart. Oestradiol measurement is typically very low, although ovarian function can resume on an unpredictable basis and produce detectable oestradiol. FSH is not an ideal diagnostic tool: it rises only in the later stages of follicle depletion, has marked cycle-to-cycle variability and is poor at predicting reproductive status.[6] There has been interest in more direct markers of ovarian reserve[7] such as anti-Mullerian hormone (AMH), which closely follows the reduction in follicle number over time in healthy women and falls to very low levels prior to menopause.[8] In assessment of amenorrhoea, AMH or transvaginal ultrasound scan will exclude polycystic ovarian syndrome as a cause. In POF, the antral follicle count is very low, and seeing this as a 'direct' marker of ovarian function may help some women understand the diagnosis. However, even in POF, the intermittent ovarian function means that follicular activity is seen in the majority of women.[9]

Aetiology

In the absence of an obvious cause of POF (oophorectomy, chemotherapy or pelvic radiotherapy), young women should be offered investigation into aetiology. However, in the majority of cases, no cause is found. Even if causation is established, the management – including fertility options – remains unchanged. Estimating the prevalence of different causes is difficult owing to the sampling bias in studies of women attending clinics. A genetic aetiology will be identified in approximately 5%[10] and autoimmune in up to 30%[9] depending on the clinic referral base.

Genetic Tests

  • A karyotype should be offered to women with POF if the onset of amenorrhoea or oligomenorrhoea is before age 25. A karyotype is also indicated in women of any age in whom Turner's syndrome mosaicism is suspected.

  • Women with POF should be offered FMR1 (fragile X) premutation testing. Overall the premutation is found in 4–5% of women with POF;[10,11] amongst those with a family history of POF, 14% have a positive result.[11] Affected individuals should be referred for genetic counselling and advised that in the event of spontaneous conception they are at risk of having a child with fragile X syndrome; three cases have been reported,[12] and another is known to the authors. There are medico-legal implications if this risk is not identified. Other issues to consider are disclosure and offering testing to other family members.

  • A full family history is important as many cases of spontaneous POF appear to be inherited; estimates vary from 4% to 31%.[13] Whilst some causative mutations have been identified,[14] it is likely that many more are as yet undiscovered, and there is no clinically available test to definitively determine whether the condition is 'genetic'.

Autoimmune Tests

Thirty per cent of cases of POF are estimated to be owing to autoimmunity.[9] Unfortunately, there is little value in assessing antiovarian antibodies, which are also prevalent in the general population.[15] Presumed autoimmune aetiology may be inferred from a family history of autoimmune disease or a positive antithyroid antibody result, which is found in approximately 24% of women with POF.[16]

Associated Medical Conditions

A wide range of medical conditions may be associated with POF. Thyroid dysfunction is common; women should have initial thyroid function tests (TFT) and antibody testing. TFT should be repeated every 2–5 years, or even annually if antithyroid antibodies are present, to detect the development of thyroid disease. It is also wise to test for antiadrenal antibodies to identify the small subgroup at risk of developing Addison's disease.[17] This is important if egg donation is being pursued because of the danger of cortisol deficiency in pregnancy. Positive results are found in approximately 3% with POF compared with 0·01% of the general population.[17]

Low bone mineral density (BMD) may result from oestrogen deficiency; DXA of the lumbar spine and hip will identify those with osteoporosis or osteopenia and provide baseline BMD to guide treatment decisions.

Further investigation, for example for Vitamin D deficiency, may be needed in selected patients.

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