Dr Louise Newson provides ten top tips on diagnosing and managing premature ovarian insufficiency in primary care

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Read this article to learn more about:

  • confirming a diagnosis of premature ovarian insufficiency
  • causes of premature ovarian insufficiency and genetic and lifestyle factors that increase risk
  • the use of sex steroid replacement therapy.

Premature ovarian insufficiency (POI) describes a continuum of declining ovarian function in young women, which results in premature onset of menopause.1 It is a common and underdiagnosed condition with profound physical and psychological consequences. Management of POI is often suboptimal, resulting in women needlessly experiencing short- and long-term symptoms and a detrimental impact on their overall health. 

This article focuses on the diagnosis and management of POI and is based on the European Society of Human Reproduction and Embryology (ESHRE) guideline on Management of women with premature ovarian insufficiency2 and NICE Guideline (NG) 23 on Menopause: diagnosis and management.3

Be aware of how common POI is

Premature ovarian insufficiency is more common than most healthcare professionals realise; approximately 1% of women aged under 40 years, 0.1% of women aged under 30 years, and 0.01% of women aged under 20 years have the condition.4 The condition is more common in Caucasian, African American, and Hispanic women compared with Japanese women.5

Know the possible underlying causes

Iatrogenic causes of POI are the most common and include:4

  • surgical removal of the ovaries
  • radiotherapy
  • chemotherapy
  • hysterectomy without oophorectomy.6

Where chemotherapy is the iatrogenic cause, POI can be temporary as ovarian function can recover, especially in younger women.7 There is now lower mortality and improving cure rates in childhood cancers, which have resulted in a rising prevalence of iatrogenic POI.8

For the majority of women with spontaneous POI, no underlying cause is identified.9 There is a strong genetic component; in around 20–30% of cases women have a family history of POI.10 Chromosomal abnormalities are more likely in women who present with primary amenorrhoea and many different genes can be involved. Abnormalities of the X chromosome (e.g. Turner syndrome) occur in around 13% of women with POI.11 Fragile X syndrome (FXS) and its associated disorders are caused by Fragile X permutation; carriers have an expansion of the CGG repeat in the 5’ untranslated region of the fragile X mental retardation 1 gene. Approximately 20% of women with FXS will develop fragile X-associated POI (FXPOI)—it is the most common genetic mutation identified in POI.12

There is an association between POI and conditions related to autoimmune dysfunction, such as Addison’s disease, type 1 diabetes mellitus, and hypothyroidism.9 Premature ovarian insufficiency is more common in women who smoke and women with a history of ovarian and pelvic surgery.13

Investigate possible POI in all women aged under 40 years with amenorrhoea

Consider POI in any woman aged under 40 years who presents with secondary amenorrhoea, oligomenorrhoea, or menstrual irregularity of more than 3 months’ duration. Many women with POI will experience typical symptoms of the menopause; however, in around one-quarter of cases women will not experience any menopausal symptoms, which makes the diagnosis less obvious.9

NICE NG23 recommends that a diagnosis of POI can be confirmed in women under 40 years based on:3

  • menopausal symptoms, including no or infrequent periods (taking into account whether the woman has a uterus) and
  • elevated FSH levels on two blood samples taken 4–6 weeks apart.
  • Routine anti-Müllerian hormone testing should not be used to diagnose POI.3

Consider the psychological effects of POI diagnosis on the patient

A diagnosis of POI can have a significantly negative impact on a woman’s psychological wellbeing and quality of life. 

Women with POI experience lower self-esteem and are at increased risk of depression and anxiety,9,14 and can also present with other psychological problems including irritability, forgetfulness, insomnia, and poor concentration.15 Psychological interventions should be accessible to women with POI.2 Multidisciplinary teams may need to be involved and the approach to treatment should be holistic.2

Prolonged low oestrogen levels in women can cause vulvovaginal atrophy (VVA). The true incidence of VVA in women with POI is not known, but it is very common. Vaginal lubricants, moisturisers, and systemic or local hormone replacement therapy (HRT) can be very effective at improving genitourinary symptoms. Some women will require local and systemic HRT in combination.2 For more information on vaginal dryness and genitourinary syndrome of the menopause, read the Guidelines in Practice top tips article.

Be aware of the potential health risks of untreated POI

There are both short- and long-term consequences of untreated POI. Short-term consequences mostly result from oestrogen deficiency and may include vasomotor symptoms, insomnia, joint pain, labile mood, low energy, low libido, and impaired memory and concentration.13 The long-term health impacts of POI include infertility, osteoporosis, cardiovascular disease (CVD), neurologic diseases, and increased mortality.14,16

Early menopause (aged under 45 years) is associated with increased risk of CVD; women who have a bilateral salpingo-oophorectomy at a younger age than the average menopause (51 years) are at even greater risk of CVD.14 Women with POI have a higher risk of premature atherosclerosis and unfavourable lipid profiles.13

Women with POI should be given lifestyle advice on reducing cardiovascular risk factors such as not smoking, undertaking regular exercise, and maintaining a healthy weight.2 Blood pressure, weight, and smoking status should all be monitored annually. 

Discuss bone health with women with POI

For optimum bone health, women with POI should be advised to maintain a healthy lifestyle that involves:2

  • weight-bearing exercises
  • avoidance of smoking
  • maintenance of normal body weight
  • a balanced diet (supplementation may be required in women with inadequate calcium and vitamin D intake).

Measurement of bone mineral density should be considered at the initial diagnosis of POI. This is particularly important in women who have additional risk factors for osteoporosis; for example, a history of low-impact fragility fractures.2

Oestrogen replacement therapy can improve bone mineral density and is therefore recommended for women with POI to maintain bone health and prevent osteoporosis.2 Both HRT and the combined oral contraceptive pill (COCP) offer bone protection;3 however, HRT has been shown to offer greater increases in bone density compared with COCP.17

Understand that HRT is safe in young women

Hormone replacement is important for treating symptoms and protecting against the long-term effects of oestrogen deficiency.2 All women with POI should be offered sex steroid replacement therapy (unless there are contraindications) and advised of the importance of continuing treatment at least until the average age of natural menopause (51 years).2,3

Options include either HRT or COCP, but it is important to note that HRT may have a beneficial effect on blood pressure compared with COCP and so is preferable for women with raised blood pressure. 

Most HRT contains 17-beta oestradiol—the active component of natural ovarian oestrogen—and is associated with fewer risks compared with the potent synthetic oestrogen analogue, ethinylestradiol, used in COCP;13 therefore, 17-beta oestradiol is preferred to ethinylestradiol (or conjugated equine oestrogens) for oestrogen replacement in women with POI.2

Patient preference for the type and route of administration of sex steroid therapy needs to be taken into consideration and individualisation of care is very important.3 Women with POI typically require higher doses of oestrogen than women who reach menopause at a later age.9

Women with POI should be informed that HRT has not been found to increase the risk of breast cancer before the age of natural menopause.2

9 Discuss the contraception needs of the patient

Spontaneous conception occurs in around 5–10% of women with POI.13 Women with POI should be informed that there is a small chance of spontaneous pregnancy and advised to use contraception if they wish to avoid pregnancy.2

Combined oral contraceptives can be beneficial for women who require contraception; however, they usually contain ethinylestradiol, which can have unfavourable effects on lipid profile, haemostatic factors, and risk of thromboembolic events.2 Concerns have been reported about the long-term effects of oestrogen deficiency in the pill-free week in women with POI taking COCP.9

For many women who require contraception, the combination of oestrogen with an intrauterine system (IUS) is often an optimal combination.9

There are no interventions that have reliably demonstrated an increase in natural conception rates, and women with POI should be informed of this.2 Oestrogen treatment may increase the ovulation rate in some women.2 For women who want to have children, IVF with donor eggs has the highest chance of success.2 Other options that could be discussed include adoption or childfree living.

10 Ensure women with POI have adequate support and information

For many women, and their partners, the diagnosis of POI can be devastating and overwhelming so it is important that healthcare professionals adopt a sensitive and caring approach.1 Consider providing women diagnosed with the condition with further information about POI, or directing them to useful online resources (see Box 1). Some women also find referral to a support group such as The Daisy Network really beneficial. Improved awareness and recognition of this condition will have a hugely positive impact on the future health and wellbeing of women with POI. 

Box 1: Useful online resources for women with premature ovarian insufficiency

Patient.info

The Daisy Network

My Menopause Doctor

POI registry

  • A database designed to collate prospective anonymised data about women with POI in order to develop a better understanding of the presentation, causes, impact, and outcomes of POI, and optimise management of the condition.
  • poiregistry.net

POI=premature ovarian insufficiency

References

  1. Fenton A. Premature ovarian insufficiency: pathogenesis and management. J Midlife Health 2015; 6 (4): 147–153.
  2. POI Guideline Development Group. Management of women with premature ovarian insufficiency. European Society of Human Reproduction and Embryology, 2015. Available at: www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-ovarian-insufficiency.aspx
  3. NICE. Menopause: diagnosis and management. NICE Guideline 23. NICE, 2015. Available at: www.nice.org.uk/ng23 
  4. Panay N, Kalu E. Management of premature ovarian failure. Best Pract Res Clin Obstet Gynaecol 2009; 23: 129–140. 
  5. Luborsky J, Meyer P, Sowers M et al. Premature menopause in a multi-ethnic population study of the menopause transition. Hum Reprod 2003; 18: 199–206.
  6. Fenton A, Panay N. Does routine gynecological surgery contribute to an early menopause? Climacteric 2012; 15 (1): 1–2.
  7. Gerval M, Horner E. Meeting the challenges of early menopause. BJFM 2014; 2 (2): 28–31.
  8. Panay N, Fenton A. Premature ovarian failure: a growing concern. Climacteric 2008; 11: 1–3 
  9. Maclaran K, Panay N; Current concepts in premature ovarian insufficiency.Women’s Health (Lond) 2015; 11 (2): 169–182. 
  10. Orlandini C, Regini C, Vellucci F et al. Genes involved in the pathogenesis of premature ovarian insufficiency. Minerva Ginecol 2015; 67 (5): 421–430.
  11. Cordts E, Christofolini D, dos Santos A et al. Genetic aspects of premature ovarian failure: a literature review. Arch Gynecol Obstet 2011; 283: 635–643. 
  12. Hoyos L, Thakur M. Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency. J Assist Reprod Genet 2016; 34 (3): 315–323
  13. Hamoda H. The British Menopause Society and Women’s Health Concern recommendations on the management of women with premature ovarian insufficiency. Post Reprod Health 2017; 23 (1): 22–35.
  14. Faubion S, Kuhle C, Shuster L, Rocca W. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 2015; 18 (4): 483–491.
  15. Sullivan S, Sarrel P, Nelson L. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause. Fertil Steril 2016; 106 (7): 1588–1599.
  16. Podfigurna-Stopa A, Czyzyk A, Grymowicz M et al. Premature ovarian insufficiency: the context of long-term effects. J Endocrinol Invest 2016; 39 (9): 983–990.
  17. Cartwright B, Robinson J, Seed P et al. Hormone replacement therapy versus the combined oral contraceptive pill in premature ovarian failure: a randomized controlled trial of the effects on bone mineral density. J Clin Endocrinol Metab 2016; 101 (9): 3497–3505. G