12.1 Introduction

Premature Ovarian Insufficiency (POI) is defined by follicular depletion that occurs under the age of 40 and is characterised by a gradual fall of hormone production by the ovary, leading to amenorrhoea and infertility. The hallmark for diagnosis is raised follicle-stimulating hormone (FSH) above 25 IU/L measured twice, at least 4 weeks apart.

Ovarian ageing normally leads to the menopause at an average of 51 years. The time of oocyte depletion is determined by the number of oocytes that has populated the ovary during embryonic life and the rate of atresia that starts prior to birth and continues until the menopause.

12.2 Clinical Presentation

POI occurs in about one in 100 women under the age of 40. It can, however, present at any age, albeit with a decreased incidence. Specifically, it is estimated that POI affects 1 in 1000 women under the age of 30 and about 1 in 10,000 women under the age of 20 years. It can therefore present in adolescence with pubertal delay, primary or secondary amenorrhoea or dysfunctional uterine bleeding (DUB) due to anovulatory cycles.

In adolescence these symptoms are often mistaken for physiological or idiopathic changes and the diagnosis may thus be delayed or masked by the administration of hormonal contraceptive methods.

POI presents a spectrum of symptoms, with shorter follicular phases, anovulation and DUB often preceding the final stage of complete ovarian silence, which is characterised by amenorrhoea.

During early stages of failure, gonadotrophin, specifically follicle-stimulating hormone (FSH), is often within a normal range. When looking closely at laboratory results, however, this is usually secondary to the production of increased oestrogen due to the presence of a functional follicular cyst or a shorter follicular phase. Therefore, high levels of estradiol during the follicular phase may be an early indirect sign of ovarian dysfunction.

During early stages, ultrasonography may reveal a smaller ovarian volume and a reduced antral follicular count or follicular cysts, whereas at a final stage, ovaries are devoid of follicles and the endometrium is thin, as a result of low oestrogen levels.

Anti-Müllerian hormone (AMH) may be used when there is suspicion of an early-stage POI and gonadotrophin levels are inconclusive. However, normal values vary depending on the stage of pubertal development, and even with lower than expected levels, it is not possible to provide a safe prediction of the rate of ovarian decline [Reference Kelsey, Wright, Nelson, Anderson and Wallace1].

12.3 Aetiology

POI may be congenital (chromosomal or genetic) or acquired (iatrogenic, infectious or autoimmune). In over 50% of cases, however, the aetiology will not be identified.

Certain known causes of POI are shown in Table 12.1.

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  Turner syndrome is the commonest chromosomal disorder identified in women with POI, affecting one in 2000 births. Diagnosis is often made antenatally, in the newborn period or childhood as a result of investigations for increased nuchal thickness, congenital cardiac anomalies, limb lymphoedema or a short stature. However, diagnosis in approximately one-third of girls will be triggered through investigations for delayed puberty and/or primary amenorrhoea.

  
  

  Turner syndrome is characterised by streak ovaries, due to an increased rate of follicular atresia. Some girls, particularly those with a Turner mosaicism, may actually retain ovarian function and develop into puberty normally. The majority, however, will eventually later develop POI and secondary amenorrhoea.

  
  

  Girls diagnosed with TS should be under regular follow-up for acquired autoimmune, metabolic and cardiac conditions, as discussed in Chapter 10.

  
  
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  Fragile X gene (FMR1) is located on the X chromosome and normally has under 45 CGG repeats at the N end of the allele. A full mutation is characterised by the presence of more than 200 repeats and leads to severe mental restriction, whereas in a premutation, repeats of 55–200 cause POI in approximately one-fourth of cases [Reference Raspa, Wheeler and Riley2].

  
  

  Fragile X premuations are more likely to be found in families where there is a strong history of POI or dementia.

  
  
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  A multitude of genetic mutations have been implicated in POI. In certain cases, the causative mutation is already known when POI is identified. For example, galactosaemia [Reference Fridovich-Keil, Gubbels, Spencer, Sanders, Land and Rubio-Gozalbo3] leads to POI in the majority of affected girls and is usually identified at birth. Syndromic features, such as those seen in blepharophimosis syndrome [Reference Nuovo, Passeri, Di Benedetto, Calanchini, Meldolesi and Di Giacomo4], are again indicative of specific gene mutations in women with POI. In other cases, gene mutations lead to gonadal dysgenesis, which usually presents with complete ovarian silence and first becomes evident with delayed puberty. Finally, certain other genetic conditions may be more common among certain populations, such as a mutation of the FSH receptor gene more commonly seen among Finnish women with POI, where follicular reserve is not affected but no oestradiol production is seen by the ovary due to resistance to FSH [Reference Tapanainen, Vaskivuo, Aittomäki and Huhtaniemi5]. These women present with delayed puberty and despite raised FSH levels they will have normal ovaries on imaging and a normal AMH level.

  
  
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  Adrenocortical antibodies lead to an autoimmune form of POI where there is lymphocytic infiltration of secondary follicles, leading to a selective destruction of theca cells. As granulosa cells remain unaffected, there is a paradoxically normal AMH, despite elevated FSH levels. On ultrasound the ovary may appear normal, as primary follicles remain intact.

  
  

  Women with autoimmune POI are at risk of developing adrenocortical insufficiency, and should be thus referred to an endocrinologist to rule out Addison’s disease [Reference Bakalov, Vanderhoof, Bondy and Nelson6].

  
  
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  Increasingly a number of young women will present into adolescence with ovarian insufficiency due to chemotherapy or radiation received in childhood for cancer treatment. Iatrogenic causes of POI are on the increase due to the increased survival rate of childhood cancer [7].

  
  
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  Mumps virus causes oophoritis, leading to transient ovarian failure. It is possible that other viral illnesses can also lead to POI, but it is often difficult to link the disease to POI as it may have been subclinical or presented long before POI is identified.

  
  
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  It is possible that many idiopathic cases of POI are due to either unknown genetic conditions or prior viral illnesses.

12.4 Diagnostic Algorithm

POI should be investigated as a cause of delayed puberty, primary or secondary amenorrhoea or where dysfunctional uterine bleeding persists beyond 2–3 years after menarche or presents in a woman that previously had regular cycles.

Confirmatory diagnosis of POI is made when FSH levels are above 25 IU/L in two consecutive measurements more than 4 weeks apart.

When POI is identified, the following investigations should be performed:

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  Karyotype

  
  
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  Fragile X premuations

  
  
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  Adrenocortical antibodies

  
  
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  Thyroid antibodies

A diagnosis of Turner syndrome should lead to a series of baseline investigations to rule out congenital or acquired cardiovascular disease, along with regular investigations for the development of metabolic and autoimmune disease.

Prior to performing genetic testing for fragile X premutations there should be extensive counselling regarding the implications of the diagnosis. In particular, other family members may need to be tested, and if women are identified as carriers they would also be at risk of developing POI or of delivering a boy with a fragile X mutation and potentially severe learning difficulties.

Specific genetic investigations for POI other than fragile X premutations are currently not recommended except where there is a known condition within a family or syndromic features suggestive of a specific genetic mutation.

If adrenocortical antibodies are detected, then the woman should be referred to an endocrinologist as she is at risk of developing Addison’s disease [8].