Premature ovarian insufficiency: clinical review

Diagnosis and management of premature ovarian insufficiency (POI), including clinical features, investigations to conduct, lifestyle and hormone treatment and prognosis.

Section 1: Epidemiology and aetiology
Section 2: Making the diagnosis
Section 3: Managing the condition
Section 4: Prognosis
Section 5: Case study
Section 6: Further resources


Premature ovarian insufficiency (POI) occurs in women aged under 40 years and is a syndrome consisting of menstrual disturbance (amenorrhea or oligomenorrhoea), elevated gonadotrophins and oestrogen deficiency.1 

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

Section 1: Epidemiology and aetiology

POI is more common than most health care professionals realise; POI occurs in around one in a hundred women under the age of 40 and around one in a thousand women under 30 in the UK.2 However, this condition is still underdiagnosed and often not optimally managed.

The term premature ovarian insufficiency encompasses both spontaneous POI and POI which occurs as a result of iatrogenic interventions, such as oophorectomy or chemotherapy.

Cessation of ovarian function in women aged between 40 and 45 years is termed early menopause.

Aetiology
POI arises from a genetically pre-determined reduced number of ovarian follicles at birth, accelerated follicular atresia or follicular dysfunction. This is different to the normal menopause, which usually occurs due to follicle depletion.

The underlying aetiology of POI is still poorly understood. For most women the underlying cause of their POI cannot be identified and they have unexplained or idiopathic POI.

Iatrogenic POI is the common known cause of POI. Causes include:

  • Surgical removal of ovaries and hysterectomy.
  • Radiotherapy.
  • Chemotherapy - this can be temporary, as recovery of ovarian function can occur, especially in younger women.

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

There is a family history of POI in around 20-30% of cases.5 X-linked chromosomal abnormalities (such as 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.6 There is often a family history of autoimmune conditions in these women.

POI may be associated with various infections. However, only mumps oophoritis has been considered a cause of POI. Cigarette smoking and lower socio-economic class are associated with increased risk of POI.7


Section 2: Making the diagnosis

Clinical features
The most common presenting symptoms of this condition are primary or secondary amenorrhoea. However, abnormal bleeding patterns such as oligomenorrhea may occur. When these irregular menstrual cycles occur during adolescence, diagnosis can be very difficult in younger women.

It is very important that POI is suspected in any woman who presents with secondary amenorrhoea of more than three months’ duration. In addition, amenorrhoea may sometimes develop after a pregnancy or after cessation of hormonal contraceptives and these women should still be investigated for POI.

 Important! Suspect POI in any woman who presents with secondary amenorrhoea of more than three months’ duration.

All clinicians should ask about possible menopausal symptoms (such as mood swings, night sweats and hot flushes) in women who present with oligomenorrhoea or amenorrhoea. However, it is important to note that although hot flushes and other vasomotor symptoms may be present, around 25% of women do not have any menopausal symptoms.2

Other symptoms may include mood changes, sleep disturbance, poor concentration, joint stiffness, dry eyes, low libido and lack of energy. Symptoms may be transient or intermittent and they can vary in their severity. This is due to the fluctuations in ovarian activity that may occur. Symptoms are less likely in young women with primary amenorrhoea.

Genito-urinary symptoms such as vaginal dryness, irritation, urinary frequency and urinary incontinence can result as a consequence of low oestrogen levels.

Investigations
Although proper diagnostic accuracy in POI is lacking, the following are usually used as diagnostic criteria:1

  • Oligomenorrhea or amenorrhea for at least 4 months and
  • An elevated FSH level > 25 IU/l on two occasions taken at least 4 weeks apart

Other investigations may include:

  • Chromosomal analysis is recommended for all women with non-iatrogenic POI
  • Fragile-X permutation testing (This requires careful counselling before the test is performed, including permission from the patient to perform the test beause a positive test can have implications for family members.)
  • 21Oh-Ab or adrenocortical antibodies (ACA) should be considered in women with POI of unknown cause or if an immune disorder is suspected
  • Thyroid (TPO-Ab) antibodies should be performed in women with POI of unknown cause or if an immune disorder is suspected
  • TSH should be measured every year in those women with a positive TPO-Ab test

Those women who have negative autoauntibody tests only need repeat tests if they develop symptoms. Routine screening for diabetes is not recommended in women with POI. There is no need to screen for infection as a possible underlying cause in women with POI.

Anti-Mullerian hormone may be a measure of reduced ovarian reserve.8,9 It is usually only undertaken if there is diagnostic uncertainty. A pelvic ultrasound is not usually helpful in making a diagnosis of POI but can sometimes be undertaken to exclude other pathology.

A dual-energy X-ray absorptiometry (DEXA) bone scan should be undertaken at diagnosis and then usually every several years to assess bone mineral density. The amount of ionising radiation used in a DEXA scan is very small. However, women with a normal bone density who are taking HRT do not always have to have subsequent DEXA scans.

Relatives of women with spontaneous POI should be referred for genetic counselling.

If there is doubt about the diagnosis of premature ovarian insufficiency, then the woman should be referred to a specialist with expertise in menopause or reproductive medicine.10


Section 3: Managing the condition

Lifestyle
Current guidelines recommend that women with POI should be considered for a referral to healthcare professionals with the relevant experience to help women manage all aspects of physical and psychological health related to their condition.

General lifestyle and dietary measures to reduce their increased risk of cardiovascular disease and osteoporosis should be undertaken. Any modifiable risk factors for cardiovascular disease need to be addressed and managed appropriately.

Women should have their blood pressure and weight measured annually. They should be given advice on smoking cessation (if appropriate), taking regular exercise (especially weight-bearing) and also maintaining or achieving a healthy weight.

Women with POI have an increased risk of depression. They have also been shown to have lower levels of self-esteem. Any associated depression or anxiety needs to be addressed and managed appropriately.

Hormone replacement therapy
Women with POI should be given replacement hormones either in the form of hormone replacement therapy (HRT) or the combined oral contraceptive pill COCP) 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 and reduce their increased risk of osteoporosis, cardiovascular, psychological and cognitive diseases.

The main goal of giving hormones to women with POI is to mimic normal physiological endocrinology with regard to oestrogen replacement.

Oral contraceptives contain the potent synthetic estrogen ethinylestradiol, which actually provides more steroid hormone than is needed for physiological replacement. This can sometimes lead to unfavourable effects on lipid profile, on haemostatic factors and be associated with an increased risk of thromboembolic events which is related both to the progestogen component and also the first pass effect of the liver.

By contrast, oestrogen replacement in HRT with 17ß oestradiol, which is the active component of the main ovarian oestrogen, is associated with fewer risks. Estradiol replacement appears to have a more beneficial effect on BMD compared to ethinylestradiol (as in the COCP) although the data are limited.

Micronised progesterone has a better cardiovascular safety profile compared to synthetic progestogens and may be associated with a lower breast cancer risk.8

Treatment with HRT can be given sequentially to induce a regular withdrawal bleed or as a continuous combined preparation to achieve amenorrhea. Women with POI will generally require higher doses of oestrogen to achieve symptom relief compared to postmenopausal women.3

Transdermal oestrogen should be considered in those women with an increased risk of VTE or stroke such as those who are obese or who have a history of migraine.

HRT is a very effective treatment to maintain bone health and prevent osteoporosis. It has also been demonstrated to reduce the risk of cardiovascular disease. HRT can improve general well-being in addition to improving vasomotor symptoms which negatively affect a woman’s quality of life.

Important! Any risks of HRT (for example, breast cancer risk) do not apply to younger women with POI taking HRT. The risk/benefit of HRT for women with POI is completely different from that of women using HRT for their menopause who are older than 51 years. It is essential that these women are made aware of this.

Fertility
Women with POI should be informed that there is a small chance of spontaneous pregnancy. These women should be therefore advised to use contraception if they wish to avoid pregnancy. Spontaneous conception occurs in around 5% of women with POI. Ovarian activity is more likely in those early in the natural history of this condition.

There are no interventions that have reliably shown to increase natural conception rates. Oestrogen treatment may increase the ovulation rate in some women. Oocyte donation is the most common option for fertility treatment in these patients.

It is important that women with idiopathic POI or following most forms of chemotherapy are reassured that if a spontaneous pregnancy does occur then it is not associated with a higher obstetric or neonatal risk compared to the general population.

Sexual and genitourinary function
Many women with POI have symptoms of atrophic vaginitis, which often improve considerably with HRT. In addition, local oestrogen treatments are also often needed.

Local oestrogen treatments are safe to be given in the long-term and should be given on a repeat prescription. Vaginal lubricants and moisturisers can also be very beneficial and should be discussed with patients. Sylk and Yes products can be prescribed and also bought from chemists or directly from the companies.

Systemic oestrogen may positively influence sexuality in women with POI. Psychosexual treatments may be of benefit for some women either in combination with HRT or as an alternative.

Testosterone replacement is often also given to these women. They should be counselled about this and be made aware that the long-term efficacy and safety of testosterone is still unknown. The recommendations states that if androgen therapy is started, then the effects of treatment should be evaluated after 3 to 6 months and should possibly be limited to 24 months.

The possible detrimental effect of POI on cognition should be discussed with those patients who are going to have a hysterectomy and/or oophrectomy under the age of 50 years.

Women should be informed that there is still a lack of good evidence to support the efficacy and safety of most alternative and complementary treatments.

They also need to be informed that alternative therapies are marketed as food supplements rather than medical treatments. This means that they are not subject to rules of standardisation (of for instance the formula and constitution of the herbal preparation), or the need for studies supporting their efficacy and safety.


Section 4: Prognosis

POI is associated with reduced bone mineral density (BMD) and osteoporosis. This has been associated with the presence, degree and duration of estrogen deficiency.

Numerous studies have shown that women with POI have an early onset of cardiovascular disease, especially coronary heart disease.11 They have an increased cardiovascular morbidity and mortality regardless of the underlying cause of their ovarian insufficiency.

Women with POI are more likely to develop early signs of endothelial dysfunction and premature atherosclerosis. Women with POI have significantly higher triglyceride and marginally lower HDL levels compared to women without this condition.

In addition, the diagnosis of POI can have a significantly negative impact on both psychological well-being and also a woman's quality of life.


Section 5: Case study

Mrs Jones is a 32 year old lady who comes to see you as she is worried her periods have stopped. She is not in a relationship and is definitely not pregnant. Her last period was seven months ago. She is not taking any contraception and is usually very fit and well.

The last few months she has less energy than she usually has and has been experiencing night sweats. She has not lost any weight and has no other symptoms.

You perform some blood tests including her FSH level and find that her FSH is raised at 37IU/l. All other blood tests are normal. You make a diagnosis of POI and discuss with her the diagnosis and need for treatment with hormones.

She is seen by the local gynaecologist who agrees with this diagnosis. She decides to take HRT in the form of an oestrogen patch and oral micronised progesterone tablets. She is advised that she needs to use contraception in future relationships.

She is subsequently found to have low testosterone levels and is given testosterone gel. Six months later she has all her energy back and is feeling significantly better. Her night sweats have also stopped completely.


Section 6: Further resources

www.patient.info - the Patient website has numerous leaflets regarding menopause, HRT and premature ovarian insufficiency for both healthcare professionals and patients.

www.thebms.org.uk - the British Menopause Society provides information on the menopause to healthcare professionals.

www.daisynetwork.org.uk - the Daisy Network is a large support group for women suffering with premature ovarian insufficiency.

www.menopausedoctor.co.uk - information for patients and GPs

  • Dr Louise R Newson is a GP and menopause expert in the West Midlands

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References

  1. POI Guideline Development Group. Management of women with premature ovarian insufficiency. 2015
  2. Maclaran K, Panay N. Current concepts in premature ovarian insufficiency. Womens Health (Lond Engl) 2015 Mar;11(2):169-82.
  3. Cox L, Liu JH. Primary ovarian insufficiency: an update. Int J Womens Health 2014 Feb 20;6:235-43.
  4. Cordts EB, Santos MC, Bianco B, et al. Are FSHR polymorphisms risk factors to premature ovarian insufficiency? Gynecol Endocrinol 2015;31(8):663-6.
  5. Orlandini C, Regini C, Vellucci FL, et al. Genes involved in the pathogenesis of premature ovarian insufficiency. Minerva Ginecol 2015 Oct;67(5):421-30.
  6. Silva CA, Yamakami LY, Aikawa NE, et al. Autoimmune primary ovarian insufficiency. Autoimmun Rev 2014 Apr-May;13(4-5):427-30.
  7. Gold EB, Crawford SL, Avis NE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013 Jul 1;178(1):70-83.
  8. Davey DA. HRT: some unresolved clinical issues in breast cancer, endometrial cancer and premature ovarian insufficiency. Womens Health (Lond Engl) 2013;9: 59-67
  9. Chang SH, Kim CS, Lee KS, et al. Premenopausal factors influencing premature ovarian failure and early menopause. Maturitas. 2007 Sep 20;58(1):19-30. Epub 2007 May 24.
  10. NICE. Menopause: diagnosis and management. NG23. November 2015.
  11. Barrett-Connor E. Menopause, atherosclerosis, and coronary artery disease. Curr Opin Pharmacol 2013;13: 186-191.

This clinical review was updated on 21.07.2016 by Dr Muffazal Rawala.

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