Premature Ovarian Insufficiency

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Synonym: premature ovarian failure

Premature ovarian insufficiency (POI) occurs in women aged under 40 years and is a syndrome consisting of amenorrhoea, elevated gonadotrophins and oestrogen deficiency. Typical symptoms found when the menopause occurs later, such as hot flushes and night sweats, may not be present.

POI is not an early menopause. The menopause is an irreversible permanent condition, whereas the cessation of ovarian function in POI may not always be permanent.

  • 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.
  • POI does not always develop by the same mechanism as the normal menopause, which is a result of follicle depletion.
  • POI arises either from a genetically predetermined reduced number of ovarian follicles at birth, an accelerated follicular atresia or follicular dysfunction.
  • The underlying aetiology is still poorly understood. In the vast majority of cases of spontaneous POI no underlying cause will be identified[1].
  • Some women develop POI due to mutations in the follicle-stimulating hormone (FSH) receptor[2].
  • Numerous studies have demonstrated the presence of mutations and polymorphisms in genes associated with development, recruitment and oocyte atresia in women with POI[3].
  • 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.
  • There is a family history of POI in around 20-30% of cases[4].
  • 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[5]. There is often a family history of autoimmune conditions in these women.
  • POI may be associated with various infections such as:
  • Cigarette smoking and lower socio-economic class are associated with increased risk of POI[6].
  • Later menarche, irregular menstruation and longer breastfeeding are all protective from POI[7].
  • The most common presentations are primary or secondary amenorrhoea[2].
  • However, abnormal bleeding patterns also include oligomenorrhoea.
  • As these irregular menstrual cycles occur during adolescence, diagnosis can be very difficult in young women[4].
  • Women often present with menstrual irregularities.
  • This condition should be suspected in any woman who presents with secondary amenorrhoea of more than three months' duration.
  • 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.
  • POI can affect many women psychologically. They can experience feelings of anger, guilt, sadness and helplessness. Relationship difficulties can occur. 
  • FSH levels should be taken. Two samples, >4 weeks apart.
  • Two raised levels (more than 40 IU/L) are diagnostic[8].
  • Women with POI have a low estradiol (usually <50 pmol/L).
  • TFTs and prolactin levels should be performed to exclude alternative pathology[1].
  • A dual-energy X-ray absorptiometry (DXA) bone scan may be undertaken at diagnosis and then every two years to assess bone mineral density.
  • Anti-Müllerian hormone may be a measure of reduced ovarian reserve[9, 10]. This is not routinely measured and is usually only undertaken if there is diagnostic uncertainty.
  • 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 transvaginal ultrasound scan.
  • Relatives of women with spontaneous POI should be referred for genetic counselling.
  • It is recommended that referral be considered to healthcare professionals with the relevant experience to help women manage all aspects of physical and psychological health related to their condition[8].
  • Women with POI may have complex physical and psychological needs; therefore, a multidisciplinary approach is very important[2].
  • 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.
  • Adequate dietary intake or supplementation of calcium (1000 mg) and vitamin D (800 IU) is recommended[1].
  • Women with POI should 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.
  • 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.
  • 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.
  • The regimen of transdermal estradiol and medroxyprogesterone acetate has been shown to restore bone mineral density to a level equal to women with normal ovarian function[11].
  • If using combined hormonal contraception for sex hormone replacement, it should be noted that:
    • Standard oral contraceptive pills contain synthetic steroid hormones at a greater dose than is required for physiological replacement.
    • There is a concern over lack of oestrogen in the hormone-free week[8].
    • In addition, they may be less effective than HRT in the prevention of osteoporosis[1].
    • The combined oral contraceptive pill is associated with an increased risk of thromboembolism.
    • For many women who still require contraception, the combination of oestrogen with an intrauterine system (IUS) is often an optimal combination.
  • Egg donation is the main treatment of choice for women who wish to attempt conception. This is sometimes from a family member.

NB: any risks of HRT associated with menopause management (for example, breast cancer risk) do not apply to younger women with POI who are taking HRT. The risk:benefit comparison of HRT for women with POI is completely different from that of women using HRT for their menopause in their 50s. It is essential that these women be made aware of this.

  • 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[1].

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.

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Further reading and references

  1. Maclaran K, Panay N; Current concepts in premature ovarian insufficiency. Womens Health (Lond Engl). 2015 Mar11(2):169-82. doi: 10.2217/whe.14.82.

  2. Cox L, Liu JH; Primary ovarian insufficiency: an update. Int J Womens Health. 2014 Feb 206:235-43. doi: 10.2147/IJWH.S37636. eCollection 2014.

  3. Cordts EB, Santos MC, Bianco B, et al; Are FSHR polymorphisms risk factors to premature ovarian insufficiency? Gynecol Endocrinol. 201531(8):663-6. doi: 10.3109/09513590.2015.1032933. Epub 2015 Aug 5.

  4. Orlandini C, Regini C, Vellucci FL, et al; Genes involved in the pathogenesis of premature ovarian insufficiency. Minerva Ginecol. 2015 Oct67(5):421-30. Epub 2015 Jun 26.

  5. Silva CA, Yamakami LY, Aikawa NE, et al; Autoimmune primary ovarian insufficiency. Autoimmun Rev. 2014 Apr-May13(4-5):427-30. doi: 10.1016/j.autrev.2014.01.003. Epub 2014 Jan 10.

  6. Gold EB, Crawford SL, Avis NE, et al; Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol. 2013 Jul 1178(1):70-83. doi: 10.1093/aje/kws421. Epub 2013 Jun 20.

  7. Chang SH, Kim CS, Lee KS, et al; Premenopausal factors influencing premature ovarian failure and early menopause. Maturitas. 2007 Sep 2058(1):19-30. Epub 2007 May 24.

  8. Menopause: diagnosis and management; NICE Guideline (November 2015 - last updated December 2019)

  9. Nelson SM; Biomarkers of ovarian response: current and future applications. Fertil Steril. 2013 Mar 1599(4):963-9. doi: 10.1016/j.fertnstert.2012.11.051. Epub 2013 Jan 8.

  10. Dewailly D, Andersen CY, Balen A, et al; The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update. 2014 May-Jun20(3):370-85. doi: 10.1093/humupd/dmt062. Epub 2014 Jan 14.

  11. Popat VB, Calis KA, Kalantaridou SN, et al; Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J Clin Endocrinol Metab. 2014 Sep99(9):3418-26. doi: 10.1210/jc.2013-4145. Epub 2014 Jun 6.